Process for the production of cannabidiol and delta-9-tetrahydrocannabinol

ABSTRACT

The present disclosure relates to the preparation of a cannabidiol compound or a derivative thereof. The cannabidiol compound or derivatives thereof can be prepared by an acid-catalyzed reaction of a suitably selected and substituted di-halo-olivetol or derivative thereof with a suitably selected and substituted cyclic alkene to produce a dihalo-cannabidiol compound or derivative thereof. The dihalo-cannabidiol compound or derivative thereof can be produced in high yield, high stereospecificity, or both. It can then be converted under reducing conditions to a cannabidiol compound or derivatives thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/034,876 filed Jul. 13, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/199,528 filed Jun. 30, 2016, and now U.S. Pat.No. 10,059,683 issued on Aug. 28, 2018, which claims the benefit of andpriority to U.S. Provisional Patent Application No. 62/191,097, filed onJul. 10, 2015, the entire contents of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present disclosure relates to the preparation of a cannabidiolcompound or a derivative thereof. The cannabidiol compound or derivativethereof can be prepared by an acid-catalyzed reaction of a suitablyselected and substituted di-halo-olivetol or derivative thereof with asuitably selected and substituted cyclic alkene to produce adihalo-cannabidiol compound or derivative thereof. Thedihalo-cannabidiol compound or derivative thereof can be produced inhigh yield, high stereospecificity, or both. It can then be convertedunder reducing conditions to a cannabidiol compound or derivativesthereof.

BACKGROUND OF THE INVENTION

More than 100 phytocannabinoids have been isolated to date. See Pertwee,et al. “Hand book of Cannabis,” Oxford University Press, First Edition2014, ISBN 978-0-19-966268-5. Phytocannabinoids are cannabinoids thatoriginate from nature and can be found in the cannabis plant. Thesecompounds have been investigated based, in part, on their availabilityfrom a natural source. The term “cannabinoids” generally refers to notonly the chemical substances isolated from C. sativa L exhibiting thetypical C21 terpenophilic skeleton, but also to their derivatives andtransformation products.

In addition to the historical and anecdotal medicinal use ofcannabinoids, the FDA has approved cannabinoid based products, such asMarinol™ and a number of other regulatory agencies have approvedSativex™. Many other cannabinoids are being investigated by themainstream pharmaceutical industry for various indications. Examples ofcannabinoids either approved for clinical use or in clinical trialsinclude Epidiolex™ (e.g., cannabidiol) for Dravet Syndrome andLennox-Gastaut Syndrome; cannabidivarin for epilepsy; andtetrahydrocannabidivarin for diabetes.

Many different routes to produce cannabinoids and related compounds havebeen reported. One route involves variations on the Lewis-acid catalyzedFriedel Crafts alkylation of olivetol with menthadienol. For example,U.S. Pat. No. 5,227,537 describes a reaction of equimolar quantities ofolivetol and menthadienol in the presence of p-toluenesulfonic acidcatalyst which resulted in a 44% yield of cannabidiol after purificationby column chromatography. U.S. Pat. No. 7,674,922 describes a similarreaction using a Lewis acid catalyst instead of p-toluenesulfonic acidwhich results in the formation of significant amounts of the unwantedcannabidiol isomer along with cannabidiol. The reaction route describedin the '922 patent resulted in a 47% yield of the desired cannabidiol, a17.9% yield of the abn cannabidiol and 23% of unreacted olivetol.

In addition, U.S. Pat. No. 3,562,312 describes improved selectivity forthe formation of cannabidiol by reacting 6-carbethoxyolivetol with aslight excess of menthadienol in methylene chloride in the presence ofdimethylformamide, dineopentylacetal as catalyst. This route resulted ina 42% yield of cannabidiol-carboxylic acid ethyl ester afterpurification by chromatography.

Another route for the preparation of cannabidiols involves the use ofcarboxylic acid esters as protecting/directing groups on olivetolanalogues. See, e.g., Crombie, L. et al., in J. Chem. Research (S) 114,(M), pp 1301-1345 (1977). In a first step, alkylresorcyl esters (e.g.,6-alkyl-2,4-di-hydroxybenzoic esters) are condensed with unsaturatedhydrocarbons, alcohols, ketones, or derivatives thereof such as enolesters, enol ethers and ketals, in high yields to give the corresponding3-substituted 6-alkyl-2,4-dihydroxybenzoic esters. These routes ofpreparation have been referred to as acid-catalyzed terpenylation. In asecond step, the intermediates with an ester function obtained in thefirst step are subjected to a decarboxylating hydrolysis, which formsthe ester-free cannabinoids.

For example, improvements in selectivity have been achieved byprotecting the 4 position of the olivetol related compounds with acarboxylic acid ester. The '922 patent describes the preparation ofethyl cannabidiolate in 82% yield and 93.3% (AUC) purity. After NaOHhydrolysis, however, the route resulted in a 57.5% yield and 99.8%purity (AUC). The '922 patent also describes the need to purify thecannabidiols formed, e.g., Δ-9-tetrahydrocannabinol, by esterificationof the free hydroxyl followed by purification of the cannabidiol ester,e.g., Δ-9-tetrahydrocannabinol ester. Purification was performed bycrystallization followed by hydrolysis of the ester to theΔ-9-tetrahydrocannabinol. Such steps were required to achieve a puritynecessary for pharmaceutical use.

The prior art demonstrates the difficulties of manufacturing cannabidiolcompounds or derivatives thereof, e.g., Δ-9-tetrahydrocannabinol, inhigh yield, high stereospecificity, or both. The causes of thesedifficulties can include the non-crystalline nature of the materialswhich renders them difficult or impossible to separate and purifywithout chromatography. Also, the aromatic portion of the cannabidiolmolecule is sensitive to oxidation. And, in one specific example, thethermodynamic stability of the Δ-9-unsaturation relative toΔ-8-unsaturation favors the formation of Δ-8 derivatives.

The present disclosure relates to the preparation of a cannabidiolcompound or a derivative thereof using a simple synthesis route toproduce a cannabidiol compound or derivative thereof in high yield, highstereospecificity, or both.

SUMMARY OF THE INVENTION

The present disclosure relates to the preparation of a cannabidiolcompound or a derivative thereof. The cannabidiol compound or derivativethereof can be prepared by an acid-catalyzed reaction of a suitablyselected and substituted di-halo-olivetol or derivative thereof with asuitably selected and substituted cyclic alkene (e.g., a cyclic alkenecontaining a 1-methyl-1-ethenyl substituent) to produce adihalo-cannabidiol compound or derivative thereof. Thedihalo-cannabidiol compound or derivative thereof can be produced inhigh yield, high stereospecificity, or both. It can then be convertedunder reducing conditions to a cannabidiol compound or derivativethereof.

The present disclosure also relates to the preparation of aΔ-9-tetrahydrocannabinol compound or derivative thereof. TheΔ-9-tetrahydrocannabinol compound or derivative thereof can be preparedby an acid-catalyzed reaction of a suitably selected and substituteddi-halo-olivetol or derivative thereof with a suitably selected andsubstituted cyclic alkene to produce a dihalo-cannabidiol compound orderivative thereof. The dihalo-cannabidiol compound or derivativethereof can be produced in high yield, high stereospecificity, or both.It can then be reacted with a Lewis acid catalyst to produce adihalo-Δ-9-tetrahydrocannabinol compound or derivative thereof. Thedihalo-Δ-9-tetrahydrocannabinol compound or derivative thereof can thenbe converted under reducing conditions to a Δ-9-tetrahydrocannabinolcompound or derivative thereof. Alternatively, the reduction andcyclization steps can be performed in reverse order.

In one embodiment, the present disclosure relates to a process for thepreparation of a compound of formula (I)

wherein a is an integer from 0 to 3;

R¹ and R² are each independently selected from the group consisting ofH, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl,heteroaryl, cycloalkyl or heterocycle;

wherein the alkyl, alkenyl, alkynyl or acyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, alkyl, —O-alkyl, NR^(A)R^(B), —S-alkyl,—SO-alkyl, —SO₂-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl orheterocycle; wherein R^(A) and R^(B) are each independently selectedfrom hydrogen and C₁₋₄ alkyl;

wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄alkyl, NR^(C)R^(D), —S-alkyl, —SO-alkyl and —SO₂-alkyl; wherein R^(C)and R^(D) are each independently selected from hydrogen and C₁₋₄ alkyl;

R³ is selected from the group consisting of H, alkyl, acyl, —SO₂-alkyl,—SO₂-aryl and —SO₂-heteroaryl; wherein the alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, alkyl, —O-alkyl, NR^(E)R^(F),—S-alkyl, —SO-alkyl, —SO₂-alkyl, aryl and heteroaryl; and wherein R^(E)and R^(F) are each independently selected from hydrogen and C₁₋₄ alkyl;wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, NR^(G)R^(H), —S-alkyl, —SO-alkyl and—SO₂-alkyl; wherein R^(G) and R^(H) are each independently selected fromhydrogen and C₁₋₄ alkyl;

each

represents a single or double bond; provided that both

groups are not double bonds, and wherein denoted, dash marks indicatethe points of attachment,

or a pharmaceutically acceptable salt or ester thereof;

the process including reacting a compound of formula (II), wherein eachX is independently selected from the group consisting of Br, F, I andCl, with a compound of formula (III) wherein R⁰ is H or OH, in thepresence of a protic or first Lewis acid catalyst to form a compound offormula (IV);

cyclizing the compound of formula (IV) by reacting the compound offormula (IV) with a second Lewis acid catalyst to form a compound offormula (V); and

reacting the compound of formula (V) with a reducing agent to form thecompound of formula (I)

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (I)

wherein a is an integer from 0 to 3;

R¹ and R² are each independently selected from the group consisting ofH, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl,heteroaryl, cycloalkyl or heterocycle;

wherein the alkyl, alkenyl, alkynyl or acyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, alkyl, —O-alkyl, NR^(A)R^(B), —S-alkyl,—SO-alkyl, —SO₂-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl orheterocycle; wherein R^(A) and R^(B) are each independently selectedfrom hydrogen and C₁₋₄ alkyl;

wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄alkyl, NR^(C)R^(D), —S-alkyl, —SO-alkyl and —SO₂-alkyl; wherein R^(C)and R^(D) are each independently selected from hydrogen and C₁₋₄ alkyl;

R³ is selected from the group consisting of H, alkyl, acyl, —SO₂-alkyl,—SO₂-aryl and —SO₂-heteroaryl; wherein the alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, alkyl, —O-alkyl, NR^(E)R^(F),—S-alkyl, —SO-alkyl, —SO₂-alkyl, aryl and heteroaryl; and wherein R^(E)and R^(F) are each independently selected from hydrogen and C₁₋₄ alkyl;wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, NR^(G)R^(H), —S-alkyl, —SO-alkyl and—SO₂-alkyl; wherein R^(G) and R^(H) are each independently selected fromhydrogen and C₁₋₄ alkyl;

each

represents a single or double bond; provided that both

groups are not double bonds, and wherein denoted, dash marks indicatethe points of attachment;

or a pharmaceutically acceptable salt or ester thereof;

the process including reacting a compound of formula (II), wherein eachX is independently selected from the group consisting of Br, F, I andCl, with a compound of formula (III) wherein R⁰ is H or OH in thepresence of a protic or first Lewis acid catalyst to form a compound offormula (IV);

reacting the compound of formula (IV) with a reducing agent to form acompound of formula (VI); and

cyclizing the compound of formula (VI) by reacting the compound offormula (VI) with a second Lewis acid catalyst to form the compound offormula (I).

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (VI)

wherein a is an integer from 0 to 3;

R¹ and R² are each independently selected from the group consisting ofH, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl,heteroaryl, cycloalkyl or heterocycle;

wherein the alkyl, alkenyl, alkynyl or acyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, alkyl, —O-alkyl, NR^(A)R^(B), —S-alkyl,—SO-alkyl, —SO₂-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl orheterocycle; wherein R^(A) and R^(B) are each independently selectedfrom hydrogen and C₁₋₄ alkyl;

wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄alkyl, NR^(C)R^(D), —S-alkyl, —SO-alkyl and —SO₂-alkyl; wherein R^(C)and R^(D) are each independently selected from hydrogen and C₁₋₄ alkyl;

R³ is selected from the group consisting of H, alkyl, acyl, —SO₂-alkyl,—SO₂-aryl and —SO₂-heteroaryl; wherein the alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, alkyl, —O-alkyl, NR^(E)R^(F),—S-alkyl, —SO-alkyl, —SO₂-alkyl, aryl and heteroaryl; and wherein R^(E)and R^(F) are each independently selected from hydrogen and C₁₋₄ alkyl;wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, NR^(G)R^(H), —S-alkyl, —SO-alkyl and—SO₂-alkyl; wherein R^(G) and R^(H) are each independently selected fromhydrogen and C₁₋₄ alkyl;

each

represents a single or double bond; provided that both

groups are not double bonds, and wherein denoted, dash marks indicatethe points of attachment;

or a pharmaceutically acceptable salt or ester thereof;

the process including reacting a compound of formula (II), wherein eachX is independently selected from the group consisting of Br, F, I andCl, with a compound of formula (III) wherein R⁰ is H or OH, in thepresence of a protic or first Lewis acid catalyst to form a compound offormula (IV); and

reacting the compound of formula (IV) with a reducing agent to form thecompound of formula (VI)

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (XI)

or a pharmaceutically acceptable salt or ester thereof;

the process including reacting a compound of formula (XII), wherein eachX is independently selected from Br, F, I or Cl, with a compound offormula (XIII) in the presence of a protic or first Lewis acid catalystto form a compound of formula (XIV);

cyclizing the compound of formula (XIV) by reacting the compound offormula (XIV) with a second Lewis acid catalyst to form a compound offormula (XV); and

reacting the compound of formula (XV) with a reducing agent to form thecompound of formula (XI)

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (XI)

or a pharmaceutically acceptable salt or ester thereof;

the process including reacting a compound of formula (XII), wherein eachX is independently selected from Br, F, I or Cl, with a compound offormula (XIII) in the presence of a protic or first Lewis acid catalystto for a compound of formula (XIV)

reacting the compound of formula (XIV) with a reducing agent to for acompound of formula (XVI); and

cyclizing the compound of formula (XVI) by reacting the compound offormula (XVI) with a second Lewis acid catalyst to form the compound offormula (XI)

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (XVI)

or a pharmaceutically acceptable salt or ester thereof;

the process including reacting a compound of formula (XII), wherein eachX is independently selected from Br, F, I or Cl, with a compound offormula (XIII) in the presence of a protic or first Lewis acid catalystto form a compound of formula (XIV); and

reacting the compound of formula (XIV) with a reducing agent to form thecompound of formula (XVI)

In the processes described above, the formed compounds can be acannibidiol or related compound. In particular, the compound of formula(I) can be ethyl cannabidiolate, delta-9-tetrahydrocannabidiol ordelta-8-tetrahydrocannabidiol. In particular, the compound of formula(IV) can be cannibidiol, cannabidivarin or1-(3-(((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)methyl)azetidin-1-yl)ethan-1-one(depicted below)

The processes of the present disclosure provide a number of advantagesover current methods. As described in the prior art, the Lewis acidcatalyzed condensation of olivetol or olivetolate esters withmenthadienol to prepare cannabidiol or cannibidiolate esters suffersfrom poor selectivity resulting low yields and mixtures of isomersrequiring tedious purification procedures. For example, the use of borontrifluoride etherate results in uncontrolled conversion of cannabidioland the cyclization of Δ-9-tetrahydrocannabinol toΔ-8-tetrahydrocannabinol. In the present disclosure, one or both of the4 and 6 positions of olivetol or derivatives thereof can be blocked witha halogen selected from the group consisting of Br, F, I and Cl. Inparticular, both positions can be blocked with a halogen selected fromthe group consisting of Br, F, I and Cl. In one embodiment, bothpositions can be blocked with a Br. In another embodiment, bothpositions can be blocked with a F. In yet another embodiment, bothpositions can be blocked with a Cl. The position can be blocked tocontrol the conversion and prevent the formation of unwanted cannabidiolisomers, such as the abn cannabidiol. In addition, the process can bedesigned, such as by using excess equivalents of an alkene relative to ahalogen substituted olivetol or derivatives thereof to form thecorresponding halogen substituted cannabidiol or derivative thereof in ahigh yield, high selectivity or both. In some embodiments, deficientamount can be used for economical purposes. The halogen substitutedcannabidiol can also remain stable and not undergo uncontrolledconversion to one or more cyclized products. The halogen substitutedcannabidiol or derivative thereof can also be easily converted to acannabidiol or derivative thereof by reacting with a suitably selectedreducing agent, under mild conditions, to yield the desired product inhigh yield, high purity or both.

The processes of the present disclosure can achieve high yield, highpurity or both without the need to use organo-aluminum Lewis acidcatalysts. The processes of the present disclosure can use a wideselection of catalysts including boron trifluoride etherate and aluminumtrichloride. The processes of the present disclosure can achieve highyield, high purity cannabinoid or derivative, or both without the needfor purification by formation of a polar ester group, crystallization ofthe resulting ester, and/or hydrolysis to purified cannabidiol orrelated derivative, or related purification. The processes of thepresent disclosure do not require additional derivatization of theisolated cannabidiol or related derivative, e.g.,Δ-9-tetrahydrocannabinol, prior to pharmaceutical use.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other advantages provided by the present disclosurewill be more fully understood from the following description ofexemplary embodiments when read together with the accompanying drawings,in which:

FIG. 1 shows exemplary synthetic pathways of the present disclosure.

FIG. 2 shows an exemplary synthesis of delta-9-tetrahydrocannabidiol.

FIG. 3 shows another exemplary synthesis ofdelta-9-tetrahydrocannabidiol.

FIG. 4 shows an exemplary synthesis of a C₃-olivetol analogue startingfrom 3,5-dimethoxybenzoic acid.

FIG. 5 shows exemplary synthetic pathways for the C3-cannabidiol andC3-tetrahydrocannabinol analogues using bromide protective groups.

FIG. 6 shows an exemplary synthetic pathway for cannabidiol usingchloride protective groups.

FIG. 7 shows an exemplary synthetic pathway for cannabidiol using iodideprotective groups.

FIG. 8 shows exemplary olefins used in coupling reactions withdibromo-olivetol.

FIG. 9 shows the structure of dibromo-olivetol coupled withcyclohex-2-enol.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to processes for the preparation of acannabidiol compound or derivatives thereof. For example, the presentdisclosure relates to processes for the preparation of cannabidiol,Δ-9-tetrahydrocannabinol, cannabidiolic acid, Δ-9-tetrahydrocannabinolicacid, intermediate compounds thereof and derivative compounds thereof.

In an embodiment, the present disclosure is directed to process(es) forthe preparation of a compound of formula (I) or pharmaceuticallyacceptable salt or ester thereof.

In one embodiment, the present disclosure relates to a process for thepreparation of a compound of formula (I)

wherein a is an integer from 0 to 3 (e.g., forming a 5, 6, 7 or 8membered ring);

R¹ and R² are each independently selected from the group consisting ofH, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl,heteroaryl, cycloalkyl or heterocycle;

wherein the alkyl, alkenyl, alkynyl or acyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, alkyl, —O-alkyl, NR^(A)R^(B), —S-alkyl,—SO-alkyl, —SO₂-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl orheterocycle; wherein R^(A) and R^(B) are each independently selectedfrom hydrogen and C₁₋₄ alkyl;

wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄alkyl, NR^(C)R^(D), —S-alkyl, —SO-alkyl and —SO₂-alkyl; wherein R^(C)and R^(D) are each independently selected from hydrogen and C₁₋₄ alkyl;

R³ is selected from the group consisting of H, alkyl, acyl, —SO₂-alkyl,—SO₂-aryl and —SO₂-heteroaryl; wherein the alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, alkyl, —O-alkyl, NR^(E)R^(F),—S-alkyl, —SO-alkyl, —SO₂-alkyl, aryl and heteroaryl; and wherein R^(E)and R^(F) are each independently selected from hydrogen and C₁₋₄ alkyl;wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, NR^(G)R^(H), —S-alkyl, —SO-alkyl and—SO₂-alkyl; wherein R^(G) and R^(H) are each independently selected fromhydrogen and C₁₋₄ alkyl;

each

represents a single or double bond; provided that both

groups are not double bonds, and wherein denoted, dash marks indicatethe points of attachment;

or a pharmaceutically acceptable salt or ester thereof;

the process including reacting a compound of formula (II), wherein eachX is independently selected from the group consisting of Br, F, I andCl, with a compound of formula (III) wherein R⁰ is H or OH (or asotherwise defined herein), in the presence of a protic or first Lewisacid catalyst to form a compound of formula (IV);

cyclizing the compound of formula (IV) by reacting the compound offormula (IV) with a second Lewis acid catalyst to form a compound offormula (V); and

reacting the compound of formula (V) with a reducing agent to form thecompound of formula (I)

In some embodiments, R⁰ can be selected from the group consisting of H,OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl,cycloalkyl or heterocycle;

wherein the alkyl, alkenyl, alkynyl or acyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, alkyl, —O-alkyl, NR^(I)R^(J), —S-alkyl,—SO-alkyl, —SO₂-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl orheterocycle; wherein R^(I) and R^(J) are each independently selectedfrom hydrogen and C₁₋₄ alkyl;

wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄alkyl, NR^(L)R^(M), —S-alkyl, —SO-alkyl and —SO₂-alkyl; wherein R^(L)and R^(M) are each independently selected from hydrogen and C₁₋₄ alkyl.

In other embodiments, R⁰ and R¹ are each independently selected from thegroup consisting of hydrogen and alkyl; wherein the alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, alkenyl, alkynyl and aryl.

In some embodiments, R² is selected from the group consisting of H, OH,protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl,cycloalkyl or heterocycle;

wherein the alkyl, alkenyl, alkynyl or acyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, alkyl, —O-alkyl, NR^(A)R^(B), —S-alkyl,—SO-alkyl, —SO₂-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl orheterocycle; wherein R^(A) and R^(B) are each independently selectedfrom hydrogen and C₁₋₄ alkyl;

wherein the aryl or heteroaryl, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄alkyl, NR^(C)R^(D), —S-alkyl, —SO-alkyl and —SO₂-alkyl; wherein R^(C)and R^(D) are each independently selected from hydrogen and C₁₋₄ alkyl.

In one embodiment, the R groups, e.g., R^(A) and R^(B), R^(C) and R^(D),etc., and the nitrogen atom to which they are bound can optionally forma 4 to 6 membered, saturated, partially unsaturated or aromatic ringstructure; wherein the 4 to 6 membered, saturated, partially unsaturatedor aromatic ring structure is optionally substituted with one, two ormore substituents independently selected from the group consisting of—COOH, C(O)—C₁₋₄ alkyl and —C(O)O—C₁₋₄ alkyl.

FIG. 1 shows exemplary synthetic pathways of the present disclosure. Thesubstituents, e.g., R groups, are defined herein. As shown in FIG. 1,the R₄ group can be selected from the group consisting of a substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted acyl,substituted or unsubstituted aryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted heterocycle or substituted or unsubstituted heteroaryl.

As used herein the term “alkyl”, whether alone or as part of asubstituent group, refers to a saturated C₁-C_(n) carbon chain, whereinthe carbon chain may be straight or branched; wherein n can be 2, 3, 4,5, 6, 7, 8, 9 or 10. Suitable examples include, but are not limited tomethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,n-pentyl and n-hexyl.

As used herein the term “alkenyl”, whether alone or as part of asubstituent group, refers to a C₂-C_(n) carbon chain, wherein the carbonchain may be straight or branched, wherein the carbon chain contains atleast one carbon-carbon double bond, and wherein n can be 3, 4, 5, 6, 7,8, 9 or 10.

As used herein the term “alkynyl”, whether alone or as part of asubstitutent group, refers to a C₂-C_(n), wherein the carbon chain maybe straight or branched, wherein the carbon chain contains at least onecarbon-carbon triple bond, and wherein n can be 3, 4, 5, 6, 7, 8, 9 or10.

As used herein the term “aryl”, whether alone or as part of asubstituent group, refers to an unsubstituted carbocylic aromatic ringcomprising between 6 to 14 carbon atoms. Suitable examples include, butare not limited to, phenyl and naphthyl.

As used herein the term “protected hydroxyl” refers to a hydroxyl groupsubstituted with a suitably selected oxygen protecting group. Moreparticularly, a “protected hydroxyl” refers to a substituent group ofthe formula —OPG¹ wherein PG¹ is a suitably selected oxygen protectinggroup. During any of the processes for preparation of the compounds ofthe present disclosure it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein the term “oxygen protecting group” refers to a groupwhich may be attached to an oxygen atom to protect said oxygen atom fromparticipating in a reaction and which may be readily removed followingthe reaction. Suitable oxygen protecting groups include, but are notlimited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl(TMS), MOM and THP. Other suitable oxygen protecting groups may be foundin texts such as T. W. Greene & P. G. M. Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991.

As used herein the term “nitrogen protecting group” refers to a groupwhich may be attached to a nitrogen atom to protect said nitrogen atomfrom participating in a reaction and which may be readily removedfollowing the reaction. Suitable nitrogen protecting groups include, butare not limited to, carbamates—groups of the formula —C(O)O—R wherein Rcan be methyl, ethyl, t-butyl, benzyl, phenylethyl, CH₂═CH—CH₂—, and thelike; amides—groups of the formula —C(O)—R′ wherein R′ can be methyl,phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives—groups ofthe formula —SO₂—R″ wherein R″ can be tolyl, phenyl, trifluoromethyl,2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene,and the like. Other suitable nitrogen protecting groups may be found intexts such as T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, John Wiley & Sons, 1991.

As used herein the term “acyl” refers to a group of the formula—CO—C_(n) wherein C_(n) represent a straight or branched alkyl chainwherein n can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

As used herein the term “heteroaryl” refers to any five or six memberedmonocyclic aromatic ring structure containing at least one heteroatomselected from the group consisting of O, N and S, and optionallycontaining one to three additional heteroatoms independently selectedfrom the group consisting of O, N and S; or a nine or ten memberedbicyclic aromatic ring structure containing at least one heteroatomselected from the group consisting of O, N and S, and optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure. Examples of suitable heteroaryl groupsinclude, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl,imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl,furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl,quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl and pteridinyl.

As used herein the term “cycloalkyl” refers to any monocyclic ringcontaining from four to six carbon atoms, or a bicyclic ring containingfrom eight to ten carbon atoms. The cycloalkyl group may be attached atany carbon atom of the ring such that the result is a stable structure.Examples of suitable cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein the term “heterocycle” refers to any four to six memberedmonocyclic ring structure containing at least one heteroatom selectedfrom the group consisting of O, N and S, and optionally containing oneto three additional heteroatoms independently selected from the groupconsisting of O, N and S; or an eight to ten membered bicyclic ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, and optionally containing one to fouradditional heteroatoms independently selected from the group consistingof O, N and S. The heterocycle group may be attached at any heteroatomor carbon atom of the ring such that the result is a stable structure.Examples of suitable heterocycle groups include, but are not limited to,azetidine, azete, oxetane, oxete, thietane, thiete, diazetidine,diazete, dioxetane, dioxete, dithietane, dithiete, pyrrolidine, pyrrole,tetrahydrofuran, furan, thiolane, thiophene, piperidine, oxane, thiane,pyridine, pyran and thiopyran.

The groups of the present disclosure can be unsubstituted orsubstituted, as herein defined. In addition, the substituted groups canbe substituted with one or more groups such as a C₁-C₆ alkyl, C₁₋₄alkyl, —O—C₁₋₄ alkyl, hydroxyl, amino, (C₁₋₄ alkyl)amino, di(C₁₋₄alkyl)amino, —S—(C₁₋₄ alkyl), —SO—(C₁₋₄ alkyl), —SO₂—(C₁₋₄ alkyl),halogen, aryl, heteroaryl, and the like.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

The compounds of the present disclosure can contain at least onehydroxyl group. These at least one hydroxyl group may form an ester withinorganic or organic acid. In particular, pharmaceutically acceptableacids. The ester(s) may form chiral carbons. The present disclosure isdirected toward all stereo-chemical forms of the compounds of thepresent disclosure, including those formed by the formation of one ormore ester groups.

In one embodiment, “a” can be 0, 1 or 2. In particular, “a” can be 1 or2. More particular, “a” can be 1.

In another embodiment, R¹ can be C₁₋₁₂ alkyl or C₁₋₁₂ alkenyl. Inparticular, R¹ can be C₁₋₄ alkyl. More particular, R¹ can be a methylgroup.

In another embodiment, R² is a C₁₋₁₂ alkyl optionally substituted with acycloalkyl or heterocycle. The substituted cycloalkyl or heterocycle canbe optionally substituted with a —COOH, —C(O)—C₁₋₄ alkyl, or —C(O)O—C₁₋₄alkyl group. In particular, R² can be a methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 2-methyloctan-2-yl groupor

In one embodiment, R² can be a n-propyl group. In another embodiment, R²can be n-pentyl group. In another embodiment, R² can be

In another embodiment, R³ is hydrogen or a C₁₋₄ alkyl. In particular, R³can be a hydrogen or a methyl group. More particular, R³ can behydrogen.

In yet another embodiment, “a” can be 1, R¹ can be a methyl group, R²can be a n-pentyl group and R³ can be hydrogen.

Examples of compounds of formula (I) include ethyl cannabidiolate,delta-9-tetrahydrocannabidiol and delta-8-tetrahydrocannabidiol.

Examples of compounds of formula (II) include 4,6-dibromo-olivetol or4,6-dibromo-divarinol.

Examples of compounds of formula (III) include menthadienol,1-hydroxymethyl-4(1-methylethenyl)-cyclohex-2-ene-1-ol, andcyclohex-2-enol. In one embodiment, the coupling of dibromo-olivetol,and related compounds as provided in the present disclosure, can beperformed using a cyclic olefin containing a double bond and ahydroxy-group at a conjugated position. Examples of compounds of formula(III) can also include a cyclic olefin containing a double bond and ahydroxy-group at a conjugated position.

In one embodiment, a suitably substituted compound of formula (II) beinga known compound or compound prepared by known methods, wherein each Xis independently selected from the group consisting of Br, F, I and Cl,particularly both X substituents are the same and are selected from thegroup consisting of Br, F, I and Cl, more particularly Br, F or Cl, ormore particularly Br or F, or even more particularly Br, can be reactedwith a suitably substituted compound of formula (III) being a knowncompound or compound prepared by known methods, wherein R⁰ is H or asuitably selected leaving group such as OH, Cl, Br, F, I, tosylate,mesylate, acetate, and the like, in particular OH. The reaction canoccur in the presence of a suitably selected protic or Lewis acidcatalyst, for example p-toluene sulfonic acid, trifluoromethanesulfonicacid, trifluoroacetic acid, acetic acid, sulfuric acid, iron(II)chloride, scandium(III) triflate, zinc chloride, aluminum chloride, andthe like. The reaction can occur neat or in a suitably selected solventor mixture of solvents, for example methylene chloride, chloroform,1,2-dichloroethane, cyclohexane, toluene, acetonitrile, tert-butylmethyl ether, or combinations thereof, and the like. The reaction canform a compound of formula (IV).

The compound of formula (IV) can be cyclized by reacting with a secondsuitably selected Lewis acid catalyst, for example BF₃ diethyl etherate,BF₃*AcOH, tri-isobutyl aluminum, and the like. The cyclization can alsobe performed using protic acids, such as p-toluene sulfonic acid. Thecyclization reaction can occur in a suitably selected solvent or mixtureof solvents, for example, methylene chloride, chlorobenzene, acetone,1,2-dichloroethanen-heptane, acetonitrile, toluene, and the like. Thecyclization reaction can form a compound of formula (V).

The compound of formula (V) can be reacted to remove the X substituentgroups, more particularly, the compound of formula (V) can be reactedwith a suitably selected reducing agent, for example, sodium sulfite,potassium sulfite, palladium/carbon in combination with hydrogen, andthe like; in the presence of a suitably selected base, such as sodiumhydroxide, triethylamine, sodium carbonate, tripotassium phosphate,potassium tert-butoxide, and the like. The reduction reaction can occurin a suitably selected polar solvent or mixture of polar solvents, ormixture of apolar and polar solvents, for example, methanol or a mixtureof methanol and water, acetonitrile, ethanol, acetone, isopropanol,n-butanol, dichloromethane, tetrahydrofuran, tert-butyl methyl ether ora mixture of organic solvent and water, and the like. The polar solventor mixture of polar solvents can also be selected from the groupconsisting of acetonitrile, methylene chloride, or combinations thereof,and the like. The reduction reaction can form the compound of formula(I).

The dihalo-compound, e.g., formula (II), can be contained in non-aqueoussolvents or a mixture of solvents such as dichloromethane, toluene,tert-butyl methyl, n-heptane, and the like. The non-aqueous solvent canalso contain a desiccating agent. The desiccating agent can be added toremove adventitious moisture from the reaction mixture. The amount ofdesiccating agent in the dihalo-compound solution can be up to about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29 or 30% (g of desiccating agent/mL ofsolvent). These values can be used to define a range, such as about 1and about 10%, or about 10 and about 20%.

In one embodiment, the amount of desiccating agent can be about 5% toabout 20% g/mL of anhydrous MgSO₄ per mL DCM. For example, a loweramount can be used, e.g., 5% g/mL, if the reagents are anhydrous, e.g.,MgSO₄, dibromo-Olivetol, pTSA. A higher amount can be used, e.g., 20%g/mL, if the reagents are mono-hydrates, e.g., dibromo-Olivetol and pTSAmono-hydrates. In one embodiment, the amount can be about 14.5% g/mL. Insome embodiments, the amount of desiccating agent can be 0% if thecompound, e.g., menthadienol, is present in excess amounts, such asgreater than about 3 eq.

The amount of desiccating agent per starting material can also beexpressed as a molar ratio of desiccating agent to starting material.The amount can be about 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1or about 5:1. These values can be used to define a range, such as about1.5:1 to about 3.5:1. In one embodiment, the ratio is about 2.8:1.

The desiccating agent can be any agent or compound that does notinterfere with the reaction and can remove moisture from the reactionmixture. The desiccating agent can be selected from the group consistingof an anhydrous inorganic salt, molecular sieve, activated charcoal,silica gel, or combinations thereof. In one embodiment, the desiccatingagent is anhydrous magnesium sulfate.

The reaction between compounds of formula (III) and formula (II) can becarried out with the relative amounts of compounds of formula (III) andformula (II) of about 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4 or 5.5equivalents of formula (III) to formula (II). These values can be usedto define a range, such as about 0.5 and about 5 equivalents, or about0.5 and about 3.5 equivalents or about 1.1 to about 1.7 equivalents.

The compound of formula (III) can be added to the compound of formula(II), or a solution containing formula (II), slowly. The compound offormula (III) can be added to the compound of formula (II), or asolution containing formula (II), over 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5,2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 16, 20 or about24 hours. These values can be used to define a range, such about 2 toabout 12 hours, or about 4 to about 8 hours. The compound can be addedin increments or portions over the time period. For example, thecompound can be added over 7 hours as follows: t=0: 0.65 eq; t=1 h:+0.65 eq; t=4 h: +0.3 eq and optionally t=7 h: +0.1 eq.

After addition, the reaction mixture can be stirred for an additionaltime. The reaction mixture can be stirred for an additional 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12,16, 20, 24, 36 or 48 hours. These values can be used to define a range,such as about 1 to about 3 hours, or about 6 to about 48 hours, or about12 to about 24 hours, or about 14 to about 18 hours.

One skilled in the art will recognize that the reaction or processstep(s) as herein described can proceed for a sufficient period of timeuntil the reaction is complete, as determined by any method known to oneskilled in the art, for example, chromatography (e.g., HPLC). In thiscontext a “completed reaction or process step” shall mean that thereaction mixture contains a significantly diminished amount of thestarting material(s)/reagent(s)/intermediate(s) and a significantlyreduced amount of the desired product(s), as compared to the amounts ofeach present at the beginning of the reaction.

During the addition, during the additional stir time or both, thereaction mixture can be held at a specific temperature or held within arange of temperatures. The reaction mixture can be held at −80° C., −70°C., −60° C., −50° C., −40° C., −30° C., −20° C., −10° C., 0° C., 10° C.,20° C., 30° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., 100° C.,110° C. or about 120° C. These values can be used to define a range,such as about −40° C. to about 40° C., or about −35° C. to about −25°C., or about −0° C. to about 50° C.

The reaction between compounds of formula (III) and formula (II) can becarried out in the presence of a protic or Lewis acid catalyst. Theprotic acid can be an alkyl sulfonic acid or an aryl sulfonic acidwherein the alkyl group can be a C₁-C₁₀ alkyl, and the aryl group can bea phenyl. The protic acid can be an alkyl-phenyl sulfuric acid orfluoro-sulfonic acid or hydrohalic acid where the halogen is F, Cl, Bror I. In one embodiment, the protic acid is p-toluenesulfonic acid,acetic acid, sulfuric acid, trifluoroacetic acid, scandium triflate,oxalic acid, benzoic acid, phosphoric acid, formic acid or combinationsthereof.

The Lewis acid catalyst can be of the general formula MY wherein M canbe boron, aluminum, scandium, titanium, yttrium, zirconium, lanthanum,lithium, hafnium, or zinc and Y can be F, Cl, Br, I, trifluoroacetate(triflate), alkoxide or combinations thereof. The Lewis acid catalystcan be selected from the group consisting of zinc triflate, ytterbiumtriflate, yttrium triflate, scandium triflate and combinations thereof.In one embodiment, the Lewis acid catalyst is a triflate, such as zinctriflate or scandium triflate.

The amount of the protic or Lewis acid catalyst, e.g., p-toluenesulfonicacid, in the reaction between compounds of formula (III) and formula(II) can be about 0.5 mol %, 1 mol %, 2 mol %, 3 mol %, 4 mol %, 5 mol%, 6 mol %, 7 mol %, 8 mol %, 9 mol %, 10 mol %, 20 mol %, 30 mol %, 40mol %, 50 mol %, 60 mol %, 70 mol %, 80 mol %, 90 mol %, 100 mol %, orabout 120 mol % with respect to the compound of formula (II). Thesevalues can be used to define a range, such as about 4 mol % to about 6mol %, 20 mol % to about 80 mol %, or about 40 mol % to about 60 mol %.

The reaction between compounds of formula (III) and formula (II) can becarried out in an organic solvent. The organic solvent can be aprotic.The organic solvent can be selected from the group consisting ofmethylene chloride, chloroform, trichloroethylene, methylene bromide,bromoform, hexane, heptane, toluene, xylene, and combinations thereof.

The compound of formula (IV) can be cyclized to form a compound offormula (V) in the presence of a Lewis acid catalyst, protic acid, orcombinations thereof.

The Lewis acid catalyst can be of the general formula MY wherein M canbe boron, aluminum, scandium, titanium, yttrium, zirconium, lanthanum,lithium, hafnium or zinc, and Y can be can be F, Cl, Br, I,trifluoroacetate (triflate), alkoxide or combinations thereof. The Lewisacid catalyst can be selected from the group consisting of zinctriflate, ytterbium triflate, yttrium triflate, scandium triflate andcombinations thereof. In one embodiment, the Lewis acid catalyst is atriflate, such as zinc triflate or scandium triflate.

The amount of Lewis acid catalyst in the cyclization reaction can beabout 0.5 mol %, 1 mol %, 2 mol %, 5 mol %, 10 mol %, 20 mol %, 30 mol%, 40 mol %, 50 mol %, 60 mol %, 70 mol %, 80 mol %, 90 mol %, 100 mol%, or about 120 mol % with respect to the compound of formula (IV).These values can be used to define a range, such as about 0.5 mol % toabout 10 mol %.

The cyclization reaction can be carried out in carried out in a suitablyselected organic solvent or mixture of organic solvents. The organicsolvent can be selected from the group consisting of a hydrocarbon,aromatic hydrocarbon, halogenated hydrocarbon, ether, ester, amide,nitrile, carbonate, alcohol, carbon dioxide, and mixtures thereof. Inone embodiment, the organic solvent is dichloromethane.

The temperature of the cyclization reaction can be held at a specifictemperature or held within a range of temperatures. The reaction mixturecan be held at −40° C., −30° C., −20° C., −10° C., 0° C., 10° C., 20°C., 30° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., 100° C.,110° C. or about 120° C. These values can be used to define a range,such as about −20° C. to about 50° C., or about 0° C. to about 30° C.

The compound of formula (V) can be reacted with a reducing agent to formthe compound of formula (I). The compound of formula (V) can bedissolved in a polar solvent and can be treated with a reducing agent inthe presence of a base to produce the compound of formula (I).

The polar solvent can be water, alcohol, or combinations thereof, e.g.,a water-alcohol mixture. The alcohol can be selected from the listconsisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol,2-butanol, 2-methyl-1-propanol and 2-methyl-2-propanol. In oneembodiment, the solvent is methanol.

As used herein, the term “reducing agent” refers to an agent having theability to add one or more electrons to an atom, ion or molecule. Thereducing agent can be a sulfur-containing compound, or Pd/C in thepresence of hydrogen. The sulfur containing compound can be asulfur-containing reducing agent having the ability to reduce C—X bondsof a compound of formula (IV) to C—H bonds.

The sulfur-containing compound can be a sulfur-containing inorganic acidor salt thereof, including, for example, hydrosulfuric acid (H₂S),sulfurous acid (H₂SO₃), thiosulfurous acid (H₂SO₂O₂), dithionous acid(H₂S₂O₄), disulfurous acid (H₂S₂O₅), dithionic acid (H₂S₂O₂), trithionicacid (H₂S₃O₆) and salts thereof. The sulfur-containing inorganic saltcan be an alkali metal salt or an alkaline earth metal salt. Forexample, the salt can be a monovalent or divalent cation selected fromLi⁺, Na⁺, K⁺, Rb⁺, Cs⁺, Fr⁺, Be²⁺, Mg²⁺, Ca²⁺, Sr²⁺, Ba²⁺, or Ra²⁺. Inone embodiment, the salt can be selected from the group consisting ofLi⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺ and combinations thereof.

The sulfur-containing inorganic salt can also be an ammonium salt (NH₄⁺) or a quaternary ammonium salt. For example, the sulfur-containinginorganic acid salt can be a tetra-alkylated ammonium salt, e.g., aquaternary ammonium salt substituted with four alkyl groups. The alkylgroups can be a C₁-C₁₈. The tetraalkylated ammonium salts can be atetramethylammonium salt, a tetraethylammonium salt, atetrapropylammonium salt, a tetrabutylammonium salt, or combinationsthereof.

The sulfur-containing inorganic acid or salt thereof can also be onewhich dissociates into a bisulfite ion (HSO₃ ⁻) and/or a sulfite ion(SO₃ ²⁻) in the reaction mixture. Sulfurous acid (H₂SO₃) can generallyexist as a solution of SO₂ (commonly about 6%) in water. The pKa ofsulfurous acid (H₂SO₃) is about 1.78 and its ionization expression is:H₂O+SO₂←→H₂SO₃←→H⁺+HSO₃ ⁻←→H⁺+SO₃ ²⁻. In one embodiment, thesulfur-containing compound is sodium sulfite.

The molar ratio amount of sulfur-containing compound to the compound offormula (IV) in the reduction reaction mixture can be about 0.8:1, 1:1,1.5:1, 2:1, 3:1, 4:1, 5:1 or greater. These values can define a range,such as about 2:1 to about 4:1, or about 2.5:1 to about 3.5:1. In oneembodiment, the ratio is about 3:1.

The base can be an organic or weak inorganic base. In one embodiment,the base can be an organic base, e.g., a tertiary amine. The base can beselected from the group consisting of trimethylamine, triethylamine,tripropylamine, diisopropylmethylamine, N-methylmorpholine,triethanolamine and combinations thereof. In one embodiment, the base istriethylamine. In another embodiment, the base can be a weak inorganicbase, e.g., a carbonate or bicarbonate salt. The base can be a carbonateor bicarbonate salt selected from the group consisting of Li⁺, Na⁺, K⁺,Mg²⁺, Ca²⁺ and combinations thereof.

The molar ratio amount of base to the compound of formula (IV) in thereduction reaction mixture can be about 0:1, 1:1, 1.5:1, 2:1, 3:1, 4:1,5:1, 6:1, 7:1, 8:1 or greater. These values can define a range, such asabout 3.5:1 to about 4.5:1, or about 4:1 to about 6:1. In oneembodiment, the ratio is about 4:1.

The reduction reaction can be carried out at a reflux temperature,including a temperature elevated by high pressure, of the solvent orsolvent mixture for a duration of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 20, 24, 28, 30, 32, 36 or about 48 hours; or any amount of timerequired to reach a desired endpoint (wherein the desired endpoint canbe determined by for example, a percent conversion of starting materialor an intermediate material). In some embodiments, the conversion of thedi-halogen to the mono-halogen proceeds faster than the conversion ofthe mono-halogen to the fully dehalogenated product. These values candefine a range, such as about 10 to about 30 hours. In one embodiment,the reduction reaction can be carried out at reflux in a methanol-watermixture for a duration of about 16 hours to about 24 hours, or about 20to about 28 hours.

The reflux temperature can be at 20° C., Room Temperature, 30° C., 40°C., 50° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95°C., 100° C., 110° C. or about 120° C. These values can be used to definea range, such as about 20° C. to about 100° C., or about RT to about 50°C., or about 60° C. to about 85° C., or about 72° C. to about 76° C. Insome embodiments, subsequent distillation can be performed. Thedistillation can be performed at the same temperatures listed above,e.g., 85° C.

The reflux pressure can be at atmospheric pressure. In some embodiments,the reflex can be done at a pressure of about 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, or about 4000mbar. These values can be used to define a range, such as about 900 toabout 3000 mbar.

The reaction products, e.g., the reduction reaction products, of thepresent disclosure can further be purified by chromatography,countercurrent extraction, distillation, or combinations thereof. Thereaction products of the present disclosure can also be purified bycrystallization.

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (I) including reacting acompound of formula (II) with a compound of formula (III) in thepresence of a protic or first Lewis acid catalyst to form a compound offormula (IV), as described above. The compound of formula (IV) can thenbe reacted with a reducing agent to form a compound of formula (VI).

The compound of formula (IV) can be dissolved in a polar solvent and canbe treated with a reducing agent in the presence of a base to producethe compound of formula (VI). The reduction reaction, conditions,components, parameters, etc. are similar to the reaction of a compoundof formula (V) reacting with a reducing agent to form the compound offormula (I), as described above.

The compound of formula (VI) can then be reacted with a second Lewisacid catalyst to form the compound of formula (I).

The cyclization reaction, conditions, components, parameters, etc. aresimilar to the cyclization reaction of a compound of formula (IV) in thepresence of a Lewis acid catalyst to form a compound of formula (V), asdescribed above.

In one embodiment, a suitably substituted compound of formula (II) beinga known compound or compound prepared by known methods, wherein each Xis independently selected from the group consisting of Br, F, I and Cl,particularly both X substituent groups are the same and are selectedfrom the group consisting of Br, F, I and Cl, more particularly Br F orCl, or more particularly Br or F, or even more particularly Br, isreacted with a suitably substituted compound of formula (III), being aknown compound or compound prepared by known methods, wherein R⁰ is H ora suitably selected leaving group such as OH, Cl, Br, F, I, tosylate,mesylate, acetate, and the like, particularly OH, in the presence of asuitably selected protic or Lewis acid catalyst, for example p-toluenesulfonic acid. The reaction can occur in a suitably selected solvent ormixture of solvents, for example methylene chloride. The reaction canform a compound of formula (IV).

The compound of formula (IV) can be reacted to remove the X substituentgroups, more particularly, the compound of formula (IV) can be reactedwith a suitably selected reducing agent, for example sodium sulfite. Thereaction can occur in a suitably selected polar solvent or mixture ofpolar solvents, for example methanol or a mixture of methanol and water.The reaction can form a compound of formula (VI).

The compound of formula (VI) can be cyclized by reacting with a suitablyselected second Lewis acid catalyst, for example BF₃, in a suitablyselected solvent or mixture of solvents, for example methylene chloride.The cyclization reaction can form a compound of formula (I).

In different embodiments, the processes of the present disclosure can beused to form compounds of the various formulas provided that either thefirst, second or both Lewis acid catalyst(s) is not an organo-aluminumLewis acid catalyst.

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (VI)

wherein a, R¹, R², R³ and

are defined above, unless otherwise specified below, or apharmaceutically acceptable salt or ester thereof. The process includesreacting a compound of formula (II), wherein each X is independentlyselected from the group consisting of Br, F, I and Cl, with a compoundof formula (III) wherein R⁰ is H or OH (or as otherwise defined herein)in the presence of a protic or first Lewis acid catalyst to form acompound of formula (IV), as described above. The compound of formula(IV) can then be reacted with a reducing agent to form a compound offormula (VI).

The compound of formula (IV) can be dissolved in a polar solvent and canbe treated with a reducing agent in the presence of a base to producethe compound of formula (VI). The reduction reaction, conditions,components, parameters, etc. are similar to the reaction of a compoundof formula (V) reacting with a reducing agent to form the compound offormula (I), as described above.

In one embodiment, “a” can be 0, 1 or 2. In particular, “a” can be 1 or2. More particular, “a” can be 1.

In another embodiment, R¹ can be C₁₋₁₂ alkyl or C₁₋₁₂ alkenyl. Inparticular, R¹ can be C₁₋₄ alkyl. More particular, R¹ can be a methylgroup.

In another embodiment, R² can be a C₁₋₁₂ alkyl optionally substitutedwith a cycloalkyl or heterocycle. The substituted cycloalkyl orheterocycle can be optionally substituted with a —COOH, —C(O)—C₁₋₄alkyl, or —C(O)O—C₁₋₄ alkyl group. In particular, R² can be a methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,2-methyloctan-2-yl group or

In one embodiment, R² can be a n-propyl group. In another embodiment, R²can be n-pentyl group. In another embodiment, R² can be

In another embodiment, R³ can be hydrogen or a C₁₋₄ alkyl. Inparticular, R³ can be a hydrogen or a methyl group. More particular, R³can be hydrogen.

In yet another embodiment, “a” can be 1, R¹ can be a methyl group, R²can be a n-propyl or n-pentyl group and R³ can be hydrogen.

Examples of compounds of formula (VI) include cannibidiol,cannabidivarin and

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (XI)(delta-9-tetrahydrocannabidiol)

or a pharmaceutically acceptable salt or ester thereof;

the process can include reacting a compound of formula (XII), whereineach X is independently selected from Br, F, I or Cl, with a compound offormula (XIII) (menthadienol) in the presence of a protic or first Lewisacid catalyst to form a compound of formula (XIV).

The reaction, conditions, components, parameters, etc. of the reactionof formula (XII) with a compound of formula (XIII) in the presence of aprotic or first Lewis acid catalyst to form a compound of formula (XIV)are similar to the reaction of a compound of formula (II) reacting witha compound of formula (III) to form the compound of formula (IV), asdescribed above.

The compound of formula (XIV) can then be cyclized by reacting thecompound of formula (XIV) with a second Lewis acid catalyst to form acompound of formula (XV).

The cyclization reaction, conditions, components, parameters, etc. ofthe reaction of formula (XIV) with a second Lewis acid catalyst to forma compound of formula (XV) are similar to the cyclization reaction of acompound of formula (IV) in the presence of a Lewis acid catalyst toform a compound of formula (V), as described above.

The compound of formula (XV) can then be reacted with a reducing agentto form the compound of formula (XI).

The compound of formula (XV) can be dissolved in a polar solvent and canbe treated with a reducing agent in the presence of a base to producethe compound of formula (XI). The reduction reaction, conditions,components, parameters, etc. of formula (XV) with a reducing agent toform a compound of formula (XI) are similar to the reaction of acompound of formula (V) reacting with a reducing agent to form thecompound of formula (I), as described above.

In one embodiment, a suitably substituted compound of formula (XII),being a known compound or compound prepared by known methods, whereineach X is independently selected from the group consisting of Br, F, Iand Cl; particularly both X substituent groups are the same and areselected from the group consisting of Br, F, I and Cl, more particularlyBr, F or Cl, or more particularly Br or F, or even more particularly Br,can be reacted with a suitably substituted compound of formula (XIII),being a known compound or compound prepared by known methods, wherein R⁰is H or a suitably selected leaving group such as OH, Cl, Br, F, I,tosylate, mesylate, acetate, and the like, particularly OH, in thepresence of a suitably selected protic or Lewis acid catalyst, forexample p-toluene sulfonic acid. The reaction can occur in a suitablyselected solvent or mixture of solvents, for example methylene chloride.The reaction can form a compound of formula (XIV).

The compound of formula (XIV) can then be cyclized by reacting with asuitably selected second Lewis acid catalyst, for example BF₃, in asuitably selected solvent or mixture of solvent for example methylenechloride. The cyclization reaction can form a compound of formula (XV).

The compound of formula (XV) can be reacted to remove the X substituentgroups, more particularly, the compound of formula (XV) can be reactedwith a suitably selected reducing agent, for example sodium sulfite; ina suitably selected solvent or mixture of solvents, for example methanolor a mixture of methanol and water. The reaction can form the compoundof formula (XI).

Certain of the disclosed compounds may exist in various stereoisomericforms. Stereoisomers are compounds that differ only in their spatialarrangement. Enantiomers are pairs of stereoisomers whose mirror imagesare not superimposable, most commonly because they contain anasymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat contain two or more asymmetrically substituted carbon atoms. “R”and “S” represent the configuration of substituents around one or morechiral carbon atoms.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity,i.e., they do not rotate the plane of polarized light.

The compounds of the present disclosure may be prepared as individualenantiomers by either enantio-specific synthesis or resolved from anenantiomerically enriched mixture. When the stereochemistry of adisclosed compound is named or depicted, the named or depictedstereoisomer can be at least 60%, 70%, 80%, 90%, 99% or 99.9% by weightpure relative to all of the other stereoisomers. Percent by weight purerelative to all of the other stereoisomers is the ratio of the weight ofone stereoisiomer over the weight of the other stereoisomers. When asingle enantiomer is named or depicted, the depicted or named enantiomeris at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure.Percent optical purity by weight is the ratio of the weight of theenantiomer over the weight of the enantiomer plus the weight of itsoptical isomer.

In another embodiment, the present disclosure can produce the compoundsof interest, e.g., compounds of formula (I), (VI), (XI), (XVI), etc., inhigh stereospecificity, from the starting materials, e.g., compounds offormula (II), etc. The stereospecificity of the processes of the presentdisclosure can be greater than about 60% ee, 75% ee, 80% ee, 85% ee, 90%ee, 95% ee, 97% ee, 98% ee, 99% ee. These values can define a range,such as about 90% ee and about 99% ee.

Compounds that can be produced by the process of the present disclosurecan include (−)-trans-cannabidiol, (−)-trans-Δ-9-tetrahydrocannabinol,(−)-trans-cannabidiolic acid, (−)-trans-Δ-9-tetrahydrocannabinolic acid,intermediate compounds thereof, derivative compounds thereof, as well asthe corresponding (+) enantiomer, and racemates.

The following table lists some of these compounds.

Structure Chemical name IUPAC

Structure Chemical name (IUPAC) (−)-CBD

(1′R,2′R)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′- biphenyl]-2,6-diol (+)-CBD

(1′S,2′S)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′- biphenyl]-2,6-diol (−)-Δ6-CBD

(1′R,2′R)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,6′-tetrahydro-[1,1′- biphenyl]-2,6-diol (+)-Δ6-CBD

(1′S,2′S)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,6′-tetrahydro-[1,1′- biphenyl]-2,6-diol (−)-Δ9-THC

(6aR,10aR)-6,6,9-trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (+)-Δ9-THC

(6aS,10aS)-6,6,9-trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (−)-Δ8-THC

(6aR,10aR)-6,6,9-trimethyl-3-pentyl- 6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol (+)-Δ8-THC

(6aS,10aS)-6,6,9-trimethyl-3-pentyl- 6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol (−)-(I)

(+)-(I)

(−)-(VI)

(+)-(VI)

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (XI)(delta-9-tetrahydrocannabidiol)

or a pharmaceutically acceptable salt or ester thereof;

the process can include reacting a compound of formula (XII), whereineach X is independently selected from Br, F, I or Cl, with a compound offormula (XIII) (menthadienol) in the presence of aprotic or first Lewisacid catalyst to for a compound of formula (XIV).

The reaction, conditions, components, parameters, etc. of the reactionof formula (XII) with a compound of formula (XIII) in the presence of aprotic or first Lewis acid catalyst to form a compound of formula (XIV)are similar to the reaction of a compound of formula (II) reacting witha compound of formula (III) to form the compound of formula (IV), asdescribed above.

The compound of formula (XIV) can then be reacted with a reducing agentto form the compound of formula (XVI).

The compound of formula (XIV) can be dissolved in a polar solvent andcan be treated with a reducing agent in the presence of a base toproduce the compound of formula (XVI). The reduction reaction,conditions, components, parameters, etc. of formula (XIV) with areducing agent to form a compound of formula (XVI) are similar to thereaction of a compound of formula (V) reacting with a reducing agent toform the compound of formula (I), as described above.

The compound of formula (XVI) can then be cyclized by reacting thecompound of formula (XVI) with a second Lewis acid catalyst to form acompound of formula (XI).

The cyclization reaction, conditions, components, parameters, etc. ofthe reaction of formula (XVI) with a second Lewis acid catalyst to forma compound of formula (XI) are similar to the cyclization reaction of acompound of formula (IV) in the presence of a Lewis acid catalyst toform a compound of formula (V), as described above.

In another embodiment, a suitably substituted compound of formula (XII),being a known compound or compound prepared by known methods, whereineach X is independently selected from the group consisting of Br, F, Iand Cl; particularly both X substituent groups are the same and areselected from the group consisting of Br, F, I and Cl, more particularlyBr, F or Cl, or more particularly Br or F, or even more particularly Br,is reacted with a suitably substituted compound of formula (XIII), beinga known compound or compound prepared by known methods, wherein R⁰ is Hor a suitably selected leaving group such as OH, Cl, Br, F, I, tosylate,mesylate, acetate, and the like, preferably OH, in the presence of asuitably selected protic or Lewis acid catalyst, for example p-toluenesulfonic acid. The reaction can occur in a suitably selected solvent ormixture of solvents, for example methylene chloride. The reaction canform a compound of formula (XIV).

The compound of formula (XIV) can be reacted to remove the X substituentgroups, more particularly, the compound of formula (XIV) can be reactedwith a suitably selected reducing agent, for example sodium sulfite. Thereaction can occur in a suitably selected solvent or mixture ofsolvents, for example methanol or a mixture of methanol and water. Thereaction can form a compound of formula (XVI).

The compound of formula (XVI) can be cyclized by reacting with asuitably selected second Lewis acid catalyst, for example BF₃, in asuitably selected solvent or mixture of solvent, for example methylenechloride. The cyclization reaction can form the compound of formula(XI).

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (XVI) (cannabidiol)

or a pharmaceutically acceptable salt or ester thereof;

the process can include reacting a compound of formula (XII), whereineach X is independently selected from Br, F, I or Cl, with a compound offormula (XIII) (menthadienol) in the presence of a protic or first Lewisacid catalyst to form a compound of formula (XIV).

The reaction, conditions, components, parameters, etc. of the reactionof formula (XII) with a compound of formula (XIII) in the presence of aprotic or first Lewis acid catalyst to form a compound of formula (XIV)are similar to the reaction of a compound of formula (II) reacting witha compound of formula (III) to form the compound of formula (IV), asdescribed above.

The compound of formula (XIV) can then be reacted with a reducing agentto form the compound of formula (XVI).

The compound of formula (XIV) can be dissolved in a polar solvent andcan be treated with a reducing agent in the presence of a base toproduce the compound of formula (XVI). The reduction reaction,conditions, components, parameters, etc. are similar to the reaction ofa compound of formula (V) reacting with a reducing agent to form thecompound of formula (I), as described above.

In another embodiment, the present disclosure relates to a process forthe preparation of a compound of formula (XX)

or a pharmaceutically acceptable salt or ester thereof, the process caninclude reacting a compound of formula (XXI), wherein each X isindependently selected from Br, F, I or Cl, with a compound of formula(XIII) in the presence of a protic or first Lewis acid catalyst to forma compound of formula (XXII); and

reacting the compound of formula (XXII) with a reducing agent to formthe compound of formula (XX)

The compound of formula (XXII) can be dissolved in a polar solvent andcan be treated with a reducing agent in the presence of a base toproduce the compound of formula (XX). The reduction reaction,conditions, components, parameters, etc. are similar to the reaction ofa compound of formula (V) reacting with a reducing agent to form thecompound of formula (I), as described above.

The present disclosure can produce the compounds of interest, e.g.,compounds of formula (I), (VI), (XI), (XVI), etc., in high yield, fromthe starting materials, e.g., compounds of formula (II). The yield ofthe process of the present disclosure can be greater than about 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 9100, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%. Thesevalues can define a range, such as about 60% to about 85%, or about 90%to about 99%.

The disclosures of all cited references including publications, patents,and patent applications are expressly incorporated herein by referencein their entirety.

When an amount, concentration, or other value or parameter is given aseither a range, preferred range, or a list of upper preferable valuesand lower preferable values, this is to be understood as specificallydisclosing all ranges formed from any pair of any upper range limit orpreferred value and any lower range limit or preferred value, regardlessof whether ranges are separately disclosed. Where a range of numericalvalues is recited herein, unless otherwise stated, the range is intendedto include the endpoints thereof, and all integers and fractions withinthe range. It is not intended that the scope of the invention be limitedto the specific values recited when defining a range.

The present invention is further defined in the following Examples. Itshould be understood that these Examples, while indicating preferredembodiments of the invention, are given by way of illustration only.

EXAMPLES Example 1—Synthesis of Cannabidiol from 4,6-dibromo-Olivetol

Cannabidiol, or(1′R,2′R)-5′-methyl-4″-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1″-biphenyl]-2″,6″-diol,was prepared according to the present disclosure.

Under a N₂ atmosphere, 4,6-dibromo-olivetol (20.08 g, 59.40 mmol),magnesium sulfate (20.00 g, 164.5 mmol, 2.77 equiv.) and para toluenesulfonic acid monohydrate (5.76 g, 29.8 mmol, 0.50 equiv.) weresuspended in CH₂Cl₂ (187.4 g) and cooled to between about −15 to −20° C.To this white suspension a clear solution of menthadienol (11.72 g,76.99 mmol, 1.30 equiv.) in CH₂Cl₂ (55.13 g) was added dropwise over 6hours. After stirring overnight at −15° C., the suspension was quenchedwith water (200.6 g). NaHCO₃ (5.01 g, 59.6 mmol, 1.00 equiv.) was addedin portions and the mixture was stirred for about 10 to 30 min at roomtemperature. The layers were separated and the aqueous layer wasre-extracted with CH₂Cl₂ (50.1 g). The organic layer was concentrated todryness (in vacuum).

The remaining viscous oil was dissolved in methanol (200 g). Thissolution was combined with a solution of Na₂SO₃ (22.3 g, 177 mmol, 3equiv.) in water (200 g). To the remaining white suspension,N,N-diethylethanamine (29.9 g, 295 mmol, 5.00 equiv.) was added and thesuspension was heated to reflux and stirred for 20 hours. Afterre-cooling of the reaction mixture to room temperature, conc. HCl (37 wt%) (16.2 g, 164 mmol, 2.78 equiv.) was added dropwise within 20 to 30min to a pH value of 6.5 (at 20° C.). N-heptane (80 g) was then added.The yellowish emulsion was stirred for about 20 min at 30° C. The layerswere separated. The aqueous layer was re-extracted with n-heptane (50g). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to have a ratio of cannabidiol to n-heptane of 1:4. Thesolution was seeded and cooled to −15° C. over about 2 to 3 hours. Theproduct was isolated and washed with n-heptane.

The remaining white solid (m=16.0 g), was re-dissolved in n-heptane (64g) at 40° C., cooled to 0° C. and stirred for 1 to 2 h at 0° C. Theproduct was isolated, washed with n-heptane and dried in vacuum at40-50° C. The obtained white crystalline powder (m=14.7 g, 79%) wasanalyzed by UPLC with 99.96 area %.

Example 2—Variation of the Chain Length (C₃H₇ and C₅H₁₁)

Synthesis of C3-olivetol analogue: The C3-analog of olivetol wassynthesized, starting from commercially available 3,5-dimethoxybenzoicacid as shown in FIG. 4. The synthesis of 3,5-dimethoxybenzoyl chloride[1] was first tested on a 1 g scale by the treatment of3,5-dimethoxybenzoic acid with 1.2 eq. of SOCl₂ in toluene at 100° C.The reaction proceeded smoothly and after 1 hour, a complete conversionwas observed on LC-MS. The solvents were evaporated and the product wasstripped twice with toluene to remove the excess SOCl₂ to yield 1.15 gof [1] (quantitative yield), which was used as such in furtherexperiments. Repetition of the reaction on 95 g scale was performed andyielded a second batch of [1] (110 g, quantitative yield).

Synthesis of 3,5-dimethoxybenzoyl chloride [1]

To a suspension of 3,5-dimethoxybenzoic acid (95 g, 521 mmol) in toluene(dry, 950 mL) was added thionyl chloride (74.4 g, 626 mmol, 45.4 ml) anda catalytic amount of DMF (0.2 mL). The mixture was heated to 100° C.and stirred for 6 hours. A clear solution was formed. The mixture wasallowed to cool to room temperature and all volatiles evaporated invacuo using a rotary evaporator. The mixture was stripped twice withfresh toluene (2×100 mL). Yield: 110 g of a brown oil (105% yield).

The preparation of N,3,5-trimethoxy-N-methylbenzamide [2] was firstinvestigated on a 1.10 g scale. To a stirred mixture of [1] (1.10 g) andN,O-dimethyl-hydroxylamine HCl in DCM was added triethylamine (3 eq.) at0° C. The mixture was allowed to warm to room temperature and stirredover the weekend. Analysis with LC-MS showed complete and cleanformation of [2]. Aqueous work-up yielded 0.95 g of a brown oil andsubsequent analysis with ¹H-NMR confirmed the structure. Repetition on110 g scale was performed and yielded a second batch of [2] (123 g,quantitative yield).

Synthesis of N,3,5-trimethoxy-N-methylbenzamide [2]

To a cold (0° C.) mixture of 3,5-dimethoxybenzoyl chloride (105 g, 523mmol) and N,O-dimethylhydroxylamine hydrochloride (61.3 g, 628 mmol) indichloromethane (1000 mL) was slowly added triethylamine (159 g, 1570mmol, 218 mL). During the addition, a thick suspension was formed(triethylamine HCl), which hindered proper stirring. Extra DCM (200 mL)was added and the mixture was stirred overnight. The reaction mixturewas washed twice with 50% diluted aqueous brine (2×500 mL) and dried theorganic phase on Na₂SO₄. Evaporated all volatiles in vacuo using arotary evaporator. Yield: 122.5 g of a brown oil (104% yield).

With [2] available, the Grignard reaction towards1-(3,5-dimethoxyphenyl)propan-1-one [3] was investigated on 0.5 g scale.At 0° C., a solution of the [2] in 2-Me-THF was added drop-wise to asolution of ethyl magnesium bromide in 2-Me-THF in 5 minutes. After 3hours, LC-MS showed the formation of two new main products (at 1.74 and2.11 min) as well as remaining starting material (at 1.86 min). The peakat 2.11 minutes showed the correct mass for [3] while the peak at 1.74minutes showed a mass of 196 in positive mode in the mass trace. Themixture was allowed to warm to room temperature and stirred overnight.Subsequent analysis with LC-MS showed no further conversion. Aqueouswork-up yielded 1.15 g of a brown oil which was purified by columnchromatography.

All components were separated and both of the newly formed products werecharacterized by LC-MS and ¹H-NMR. In this manner, a batch of [3] (0.11g of a colorless oil) was obtained and the structure was confirmed. Ofthe unknown side product, 0.04 g was isolated as a white solid. Both theobserved mass in LC-MS and the H-NMR spectrum indicated that thiscompound was an amide. The ¹H-NMR spectrum and appearance are inagreement with the literature (J. Am. Chem. Soc., 2014, 136, 6920-6928).The formation of this side product can be explained by deprotonation ofthe methoxy-group of the Weinreb amide by the basic Grignard reagent,leading to demethoxylation.

With all reaction products known, repetition on a 0.36 g scale wasperformed wherein solution of the [2] in 2-Me-TH was added dropwise to asolution of ethyl magnesium bromide (1.1 eq.) in 2-Me-TH at 0° C. Afterstirring for 2 hours, LC-MS showed a very similar pattern to theprevious experiment with 47 area % [3], 24 area % of the3,5-dimethoxy-N-methylbenzamide and 27 area % remaining startingmaterial. A second aliquot of ethyl magnesium bromide (1.1 eq.) wasadded and the mixture was allowed to warm to room temperature overnight.Subsequent analysis with LC-MS showed a complete consumption of [2] andthe formation of a 1:1 mixture of [3] and3,5-dimethoxy-N-methylbenzamide. Unfortunately, the initial selectivitytowards [3] observed in the earlier sample was no longer found.

The Grignard reaction towards [3] was continued without furtheroptimization and to remove the formed amide side product by columnchromatography. Thus, on 120 g scale, [2] was treated with ethylmagnesium bromide at 0° C. No problems were encountered and [3] wasformed as expected in a 59:36 ratio with the3,5-dimethoxy-N-methylbenzamide. Aqueous work-up yielded 97 g of a brownoil which was purified by column chromatography using silica andheptane:ethyl acetate (4:1) as eluent to yield 47 g of [3] as acolourless oil in 45% yield. The oil crystallized upon standing andanalysis with LC-MS showed that the purity was 97%.

Synthesis of 1-(3,5-dimethoxyphenyl)propan-1-one [3]

To a cold (0° C.) solution of N,3,5-trimethoxy-N-methylbenzamide (120 g,533 mmol) in 2-Me-THF (1000 mL) was slowly added ca. 3.2 M solution ofethylmagnesium bromide in 2-Me-THF (608 mmol, 190 mL) in 4 hours. Afterstirring for an additional 30 minutes, LC-MS showed partial conversion.Slowly ca. 3.2 M solution of ethylmagnesium bromide (64.0 mmol, 20 mL)was added. The mixture was stirred for another 30 minutes, then allowedto slowly warm to room temperature and stirred overnight. The reactionmixture was poured into 1M aq. HCl (800 mL). The layers were separatedand the aqueous phase was extracted with ethyl acetate (250 mL). Thecombined organic layers were washed with brine (250 mL), then dried onNa₂SO₄. All volatiles were evaporated in vacuo using a rotaryevaporator. Un-purified Product yield: 97 g of a brownish oil containinga white solid. The isolated product was purified by gravity columnchromatography (silica; eluent: heptane/ethyl acetate=4:1). Yield: 47 gof a colorless oil (45% yield). The oil crystallized spontaneously uponstanding for 2 days. LC-MS: purity 98%, [M+H]=195.

With this material available, a Wolf-Kishner reduction towards1,3-dimethoxy-5-propylbenzene [4] was performed on 0.5 g scale. [3] wastreated with 2 equivalents of hydrazine in refluxing ethanol asdescribed for this compound in J. Med. Chem., 1991, 34 (11), p3310-3316. After 5 hours, a nearly complete conversion into the desiredimine intermediate was observed with LC-MS. All volatiles wereevaporated using a rotary evaporator and the resulting oil was heated to230° C. in the presence of KOH (7.5 eq.) in the melt. After heating for1 hour, the mixture was cooled to room temperature overnight. Uponcooling, a white solid (KOH) with a slightly yellow oil on top wasformed. A sample of the oil was analysed with LC-MS which showed acomplete conversion and exclusive formation of [4].

The oil was separated from the solids by decanting. The oil wasdissolved in ethyl acetate and washed with 1M aq. HCl. After drying overNa₂SO₄ and evaporation of the solvents, a yellow oil was obtained (0.23g, 49%). Analysis with ¹H-NMR confirmed the structure. Repetition of thereaction on 46 g scale was performed and a complete conversion wasachieved. After aqueous work-up, [4] was obtained as a yellow oil inmoderate yield (21.1 g, 49%) and acceptable purity (93% according toLC-MS) without any additional purification.

Summary of 1,3-dimethoxy-5-propylbenzene [4]

A mixture of 1-(3,5-dimethoxyphenyl)propan-1-one (46 g, 237 mmol) andhydrazine monohydrate (23.71 g, 474 mmol, 23.07 ml) in ethanol (2.5 ml)was heated to reflux and stirred for 6 hours. All volatiles were invacuo using a rotary evaporator to yield a yellow oil. Potassiumhydroxide (100 g, 1776 mmol) was added and heated the resulting mixtureto 230° C. for 30 minutes. The mixture was allowed to cool to roomtemperature, dissolved in water (250 mL) and then extracted three timeswith diethyl ether (3×100 mL). The combined organic layers were dried onNa₂SO₄ and all volatiles were evaporated in vacuo using a rotaryevaporator. Yield: 21.1 g of a yellow oil (49% yield). LC-MS: purity93%, [M+H]=181. ¹H-NMR δ (CDCl₃): 6.35 (d, J=2.2 Hz, 2H), 6.30 (t, J=2.2Hz, 1H), 3.78 (s, 6H), 2.53 (t, J=7.5 Hz, 2H), 1.63 (sextet, J=7.4 Hz,2H), 0.94 (t, J=7.3 Hz, 3H).

With [4] available, a 0.5 g scale test reaction for thebis-demethylation (based on Molecules, 2014, 19, 13526-13540) wasperformed by heating [4] in a melt at 200° C. with pyridine HCl for 3hours. A complete conversion was observed on LC-MS and the desired masswas found in the MS trace. After aqueous work-up,5-propylbenzene-1,3-diol [5] was isolated as a yellow oil in moderateyield (0.25 g, 59%) but in good purity (94% according to LC-MS) withoutany additional purification. Repetition on 21 g scale was performed, butthe reaction could not be driven to completion, with 11% of [4]remaining after prolonged heating. After aqueous work-up, [5] (16.5 g)was obtained with a purity of only 73% (according to LC-MS).Purification using an automated Reveleris® chromatography system (120 gsilica cartridge, heptane:ethyl acetate as eluent) yielded [5] as ayellow oil in moderate yield (11.6 g, 65%) but high purity (96%according to LC-MS). The oil spontaneously crystallized upon standing.The structure of the [5], the C3-olivetol analogue, was confirmed by¹H-NMR. The preparation of a [5], the C3-olivetol analogue, startingfrom commercially available 3,5-dimethoxybenzoic acid, was performedsuccessfully.

Synthesis of 5-propylbenzene-1,3-diol [5]

A mixture of 1,3-dimethoxy-5-propylbenzene (21 g, 117 mmol) and pyridinehydrochloride (67.3 g, 583 mmol) was heated to 200° C. for 4 hours, thenallowed to cool to room temperature overnight. Water (100 mL) was addedand the mixture was extracted three times with diethyl ether (3×100 mL).The combined organic phase was dried on Na₂SO₄ and all volatilesevaporated in vacuo using a rotary evaporator. Un-purified Productyield: 16.5 g brown oil. The brown oil was purified by columnchromatography (120 g silica; eluent: heptane/ethyl acetate; gradient:t=0 min. 20% ethyl acetate, t=35 min. 50% ethyl acetate). Yield: 11.6 gof a yellow oil (65% yield). The oil slowly crystallized upon standing.LC-MS: purity 96%, [M+H]=153. ¹H-NMR δ (CDCl₃): 6.25 (d, J=2.2 Hz, 2H),6.18 (t, J=2.2 Hz, 1H), 5.44 (broad s, 2H), 2.45 (t, J=7.4 Hz, 2H), 1.58(sextet, J=7.4 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 3—Generality of Di-Halo Protection of Olivetol

The use of bromide, chloride and iodide was investigated as providingdi-halo protection to 5-propylbenzene-1,3-diol [5], the C3-olivetolanalogue.

Adding bromide as protection group: The bromination of [5] towards4,6-dibromo-5-propylbenzene-1,3-diol [6] was performed as shown in FIG.5. At −30° C., a solution of 0.25 g of [5] in 6 ml DCM was treated with2.0 eq. of bromine. During cooling of the initial starting materialsolution, a sticky oil had formed at the bottom of the flask whichhindered proper stirring. Also, the bromine was added using a syringe.The low temperature inside the reaction flask caused the bromine tosolidify in the needle and blocked it. In a subsequent experiment, abigger stirring magnet was used and the bromine was added as a solutionin DCM using a dropping funnel in 10 minutes. After stirring for anadditional 10 minutes, the reaction mixture was poured into a coldaqueous sodium thiosulfate solution. A cloudy DCM layer was formed.Addition of ethyl acetate did not remove the cloudiness. Addition ofdiethyl ether resulted in two clear layers. The layers were separated,the aqueous phase extracted once with diethyl ether. After evaporationof the solvents, [6] was obtained as an off white solid in moderateyield (0.40 g, 79%) but in good purity (94%, according to LC-MS). Themass of the [6] was also found in the mass trace with no mono- ortri-bromo compound detected. The structure was confirmed by ¹H-NMR andfurther analysis with HMBC-NMR only showed interactions between thearomatic proton and aromatic carbons and not between any aliphaticcarbons, thereby confirming the structure.

Repetition of the bromination on 1 g scale was performed using amechanical top stirrer. After work-up, a second amount of [6] wasobtained in moderate yield (1.67 g, 82%) and analysis by LC-MS showedthat the purity was 93%. Repetition on 10 g scale gave completeconversion but two impurities were observed in the LC-MS chromatogram inlarger amounts than in earlier experiments. Nevertheless, this materialwas used as such in the subsequent coupling with menthadienol towardscompound [7].

Synthesis of 4,6-dibromo-5-propylbenzene-1,3-diol [6]

A solution of 5-propylbenzene-1,3-diol (1 g, 6.57 mmol) indichloromethane (20 ml) was cooled to −50° C. Initially, a suspensionwas formed but upon further cooling, the starting material precipitatedas a sticky oil. Additional DCM (˜5 mL) was added to allow for properstirring. Then, a solution of bromine (2.111 g, 1.32 mmol, 0.679 ml) indichloromethane (20 ml) was added drop wise in 15 minutes using a dosingfunnel and the resulting mixture was stirred for 15 minutes. Thetemperature was kept below −50° C. during the reaction and subsequentstirring. The reaction mixture was poured into a cold (0° C.) solutionof sodium thiosulfate (0.519 g, 3.29 mmol) in water (20 ml) and stirredvigorously until any bromine color had disappeared. During stirring, asuspension was formed in the DCM phase. The biphasic system wasextracted with diethyl ether (50 mL) and the layers were separated. Theaqueous phase was extracted once more with diethyl ether (50 mL) and thecombined organic layers were dried on Na₂SO₄ and all volatiles wereevaporated in vacuo using a rotary evaporator. Yield: 1.67 g off-whitesolids (82% yield). LC-MS: purity 96%, [M+H]=309. ¹H-NMR δ (400 MHz,CDCl₃): 10.20 (s, 2H), 6.57 (s, 1H), 3.36 (s, 1H), 2.93-2.78 (m, 2H),2.56-2.44 (m, 2H), 1.57-1.41 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).

The coupling with menthadienol towards(1′R,2′R)-3,5-dibromo-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol[7] was first tested on a 1.6 g scale, prior to the 10 g scale reaction.[6] was treated with menthadienol (1.0 eq.) at −30° C. in the presenceof MgSO₄ and p-toluenesulfonic acid in DCM. Conversion into a newproduct with the correct mass was observed with LC-MS and by theaddition of extra menthadienol in two portions (0.25 and 0.125equivalents respectively), the reaction was driven to completion. Aftersubsequent aqueous work-up and stirring in methanol to precipitate sideproducts, [7] was isolated as a yellow oil in quantitative yield (2.36g, 99%). LC-MS indicated that the purity was 93% and the structure wasconfirmed with ¹H-NMR.

Repetition of the coupling with menthadienol on 10 g scale wasperformed. The formation of an unknown side product was found in thefinal stage of the reaction. After aqueous work-up and subsequentprecipitation of side products in methanol, the isolated product (22.7g, 90%) had a purity of only 63% according to LC-MS. The unknown sideproduct was investigated was an intermediate that is formed as thereaction proceeds via a rearrangement mechanism. Treatment withp-toluenesulfonic acid was performed to facilitate the quantitativeconversion of this intermediate towards [7]. A 100 mg sample of thebatch was dissolved in DCM and treated with 0.25 equivalents ofp-toluenesulfonic acid at 0° C. After stirring for 4 hours, noconversion was observed with LC-MS. The mixture was allowed to slowlywarm to room temperature and stirred overnight. LC-MS showed noconversion. The experiment was stopped and the mixture was discarded.

To purify the material further, column chromatography over silica andwith heptane/ethyl acetate as eluent was attempted. No separation wasachieved and only baseline material was removed in this manner. Allproduct containing fractions were collected again and concentrated toyield 17 g of a dark yellow oil.

A sample (0.5 g) was subjected to reversed phase column chromatography(40 g, C18 silica) using a Reveleris® system and MeCN/water (with 0.1%formic acid) as eluent. Sufficient separation of the two main componentswas achieved and the product containing fractions were collected and allvolatiles evaporated to yield 0.15 g of [7] as a yellow oil. Subsequentanalysis showed that the purity was 99%. The fractions containing theunknown side product were also combined and concentrated but during thisoperation, the material decomposed.

The entire batch of material was purified using reversed phase columnchromatography in 1.5 g portions using a 120 g C18 silica column andMeCN/water (with 0.1% formic acid) as eluent. In this manner, 7.7 g(30%) of [7] was obtained as a yellow oil with a purity of 99% accordingto LC-MS.

The fractions containing the unknown side product were combined and thenlyophilized to remove the solvents and to avoid decomposition. 2.14 g ofan off-white solid was obtained. Subsequent analysis with LC-MS showedthat this compound was 92% with about 7% of [7] as the main impurity. Nomass was observed in the mass trace. Further analysis with ¹H-NMR wasinconclusive It is believed that this molecule is comprised of 1molecule of the dibromo-n-propylresorcinol and 2 molecules of thementhadienol. After being exposed to air (after lyophylization), thesolid turned dark purple within 1 hour.

Synthesis of(1′R,2′R)-3,5-dibromo-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol[7]

A mixture of 4,6-dibromo-5-propylbenzene-1,3-diol (1.67 g, 5.39 mmol),(1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol (0.820 g, 5.39 mmol)and magnesium sulfate (1.621 g, 13.47 mmol) in dichloromethane (18 mL)was cooled to −35° C. Then, p-toluenesulfonic acid monohydrate (0.512 g,2.69 mmol) was added in one portion and the resulting mixture wasstirred at −35° C. The reaction was monitored with LC-MS and over thecourse of 5 hours, extra aliquots of(1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol (0.205 g, 1.347 mmoland 0.103 g, 0.673 mmol respectively) were added before allowing themixture to slowly warm to room temperature overnight. The reactionmixture was poured into a solution of dibasic potassium phosphate (0.845g, 4.85 mmol) in water (18 mL) and the layers were separated. Theaqueous phase was extracted with DCM (18 mL) and the combined organiclayers were passed through a phase separator. Then, all volatiles wereevaporated in vacuo using a rotary evaporator. Un-purified yield: 2.951g of a yellow oil. The obtained oil was dissolved in methanol (10 mL)and then stirred for 1 hour at 0° C. The white solid was removed byfiltration using a folded paper filter and was discarded. The clearfiltrate was evaporated to dryness (in vacuo) using a rotary evaporator.Yield: 2.36 g yellow oil (99% yield). LC-MS: purity 93%, mass notdetected due to poor ionization of the compound. ¹H-NMR δ (400 MHz,DMSO-d₆): 8.87-8.21 (m, 2H), 5.15 (s, 1H), 4.45 (d, J=8.7 Hz, 2H), 4.03(d, J=8.9 Hz, 1H), 3.05-2.93 (m, 1H), 2.88-2.76 (m, 2H), 2.29-2.16 (m,1H), 2.12-2.08 (m, 1H), 1.99-1.95 (m, 1H), 1.77-1.55 (m, 6H), 1.55-1.42(m, 3H), 0.96 (t, J=7.3 Hz, 3H).

Debromination of [7] towards(1′R,2′R)-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol[8], or the desired C3-cannabidiol derivative, was performed on 0.5 gscale. A mixture of [7], L-ascorbic acid (0.15 eq.), sodium sulfite(2.65 eq) and triethylamine in methanol/water was heated to 75° C. for18 hours. Analysis with LC-MS showed complete conversion but also showedthe formation of several side products. After aqueous work-up, a brownoil was obtained in good yield (307 mg, 95%) but the purity was only73%, according to LC-MS. The oil was purified by column chromatographyusing a Reveleris® system to yield a purified fraction (72 mg, 22%) as alight yellow brown oil. Analysis of this material with LC-MS indicatedthe purity was 96% and the structure was confirmed by analysis with¹H-NMR.

Repetition on 1.8 g scale initially yielded 0.46 g product (39%) as ayellow oil that spontaneously partially solidified. Analysis with LC-MSshowed that the purity was 84%. Further investigations to the work-upprocedure showed that a lot of product remained in the aqueous phase,which was therefore extracted with DCM instead of heptane. Thistreatment furnished a second amount of material (0.56 g, 48%) as ayellow oil, bringing the total yield up to 87%.

Both amounts of [8] were combined and attempts were made to crystallizethe product from heptane, heptane/DCM, heptane/DIPE and methanol/watermixtures. None of the crystallizations worked. All material wascollected again and purified by column chromatography using a Reveleris®system to yield 0.58 g (50%) of [8] as a light brown oil, whichsolidified spontaneously upon standing. Analysis with LC-MS confirmedthe mass and showed the purity to be 97%. The structure was confirmed by¹H-NMR. Broad signals in the aromatic region were observed likely aresult of hindered rotation around the benzylic C—C bond.

Repetition of the debromination on 7 g scale was carried out at 40° C.for 2 hours and the mixture was then analyzed with LC-MS. The partialremoval of only 1 bromide group was observed at this stage. Thetemperature was increased to 75° C. for 1 hour, which resulted in anearly complete conversion of the starting material and the formation ofthe mono-debrominated compound. The mixture was then stirred at 75° C.for a longer period and was monitored over time. After 16 hours, analmost complete debromination was achieved. The removal of the secondbromine group was more difficult than the first group, but a fullconversion was achieved.

Aqueous work-up and extraction with DCM yielded 5.1 g of product as ayellow oil that spontaneously partially solidified. This material waspurified by column chromatography to yield [8] (3.5 g, 78%) as aslightly yellow oil that spontaneously solidified. Analysis with LC-MSshowed the purity to be 99% and the correct mass was observed in themass trace. Further analysis with ¹H-NMR confirmed the structure andshowed the presence of 6 w/w % heptane. The analytical data of theprepared compound matched with the data obtained from a commercialreference sample.

Synthesis of(1′R,2′R)-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol[8]

To a solution of(1′R,2′R)-3,5-dibromo-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol(1.8 g, 4.05 mmol) in methanol (15 ml) was added a solution of sodiumsulfite (1.353 g, 10.74 mmol) and L-ascorbic acid (0.107 g, 0.608 mmol)in water (15 mL). A suspension was formed that later formed a sticky oilthat hindered proper stirring. To the suspension, triethylamine (1.476g, 14.59 mmol, 2.028 ml) was added in one portion which caused thesticky oil to dissolve just enough to allow proper stirring. Theresulting mixture was heated to 75° C. for 18 hours. After cooling toroom temperature, the reaction mixture was partially concentrated invacuo, using a rotary evaporator, to remove most of the methanol andvolatiles. The pH of the remaining aqueous phase was adjusted to ˜2 withconcentrated hydrochloric acid. Heptane (25 mL) was added and themixture was stirred for 30 minutes. The layers were separated, theorganic phase was washed with brine (25 mL) and then evaporated in vacuousing a rotary evaporator. Un-purified yield: 0.46 g yellow oil. The oilpartially solidified spontaneously. The remaining aqueous phase stirredwith DCM (25 mL) for 30 minutes. The layers were separated, the organicphase was washed with brine (25 mL) and then evaporated in vacuo using arotary evaporator. Un-purified yield: 0.56 g yellow oil. The oilpartially solidified spontaneously. Both oils were combined and purifiedby column chromatography (silica, eluent: heptane/ethyl acetate). Yield:0.58 g of a light brown oil (50% yield). The oil solidified uponstanding. LC-MS: purity 97%, [M+H]=287. ¹H-NMR δ (400 MHz, CDCl₃): 6.27(s, 1H), 6.17 (s, 1H), 5.98 (s, 1H), 5.57 (s, 1H), 4.70-4.50 (m, 3H),3.82-3.86 (m, 1H), 2.47-2.34 (m, 3H), 1.87-1.72 (m, 5H), 1.70-1.63 (m,4H), 1.62-1.52 (m, 3H), 0.90 (t, J=7.3 Hz, 3H).

The ring-closures of both [7] and [8] towards the C3-THC analogues [9]and [10], shown in FIG. 5, was performed. Both ring-closures werescreened on 50 mg scale using both [7] and [8] as the substrate. Table 1list the results of the screening as monitored with LC-MS.

TABLE 1 Overview of ring-closure reactions. # Substrate ConditionsResult 1 7 1 eq. p-TosOH, 17% of a new product with DCM, rt, 18 h.correct mass 2 7 1 eq. p-TosOH, decomposition toluene, 100° C., 18 h 3 71.2 eq. BF₃ etherate, near complete conversion into DCM, −10° C., 2 h.new product with correct mass, some decomposition 4 8 1 eq. p-TosOH,toluene, decomposition 100° C., 18 h 5 8 1.2 eq. BF₃ OEt₂, near completeconversion into DCM, −10° C., 2 h. new product with correct mass, nodecomposition

From these results, it was found that the use of p-toluenesulfonic acidin toluene at elevated temperature did not induce an effectivering-closure reaction. At a lower temperature, however, the use ofp-toluenesulfonic acid did lead to the formation of a new product withthe correct mass but only in 17% estimated yield. Using BF₃ etherate acomplete conversion was achieved with both substrates. These reactionmixtures, e.g., 3 and 5, were subjected to an aqueous work-up and theproducts were isolated. In this manner, 28 mg (56% yield) and 39 mg (78%yield) of [9] and [10] respectively were obtained as yellowish oils.

Analysis with LC-MS showed the correct masses of [9] and [10], andpurities of 90 and 97%, respectively. The oils were stored overnight atroom temperature. In the case of experiment 3 for [9], the oil hadturned dark brown/purple and analysis with LC-MS showed that thematerial had decomposed. In the case of experiment 5 for [10], the oilhad partly solidified. Analysis with ¹H-NMR showed that the correctcompound was formed but some impurities, that were not observed withLC-MS, still remained.

Experiment 5 for [10] was repeated on 1.3 g scale. After 90 minutes ofreaction time (at −10° C.), a clean and near complete conversion wasachieved. Aqueous work-up and extraction yielded the product as ayellow/brownish oil (1.43 g, 102% yield) with a purity of 96% accordingto LC-MS. The product was purified by Reveleris® column chromatography(using silica and heptane/ethyl acetate as eluent) to yield a slightlyyellow oil (1.33 g, 95% yield). Analysis with LC-MS showed one mainsignal in 97% with the correct mass and the other peak originating fromunreacted [8]. Analysis with H-NMR showed several unexpected signalsthat indicate that a closely related compound was present in theobtained material, as well as some residual ethyl acetate. Furtheranalysis with analytical HPLC revealed that a second product (22%) waspresent with a minute difference in retention time, again indicatingthat the impurity is closely related to the product.

It is known that A9-THC is capable of acid-catalyzed isomerization tothe thermodynamically more stable A8-THC regio-isomer. The separation ofA8- and A9-THC is also known to be challenging, requiring multiplechromatographic steps. It is believed that the unknown impurity is theA8-isomer of [10]. Despite the presence of the impurity, the theformation of [10] via the sequence [7]-[8]-[10] was demonstrated.

Synthesis of(6aS,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol[7]-[8]-[10]

To a cold (−10° C.) solution of boron trifluoride etherate (ca. 48% BF₃,0.833 g, 5.87 mmol, 0.743 mL) in dichloromethane (20 ml) was slowlyadded a solution of(1′R,2′R)-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol(1.4 g, 4.89 mmol) in dichloromethane (10 ml) in 15 minutes. Afterstirring for 90 minutes, the reaction mixture was quenched by additionof water (20 mL). The formed slurry was diluted with extra DCM (25 mL)and the layers were separated. The aqueous phase was extracted once withfresh DCM (25 mL) and the combined organic layers were dried on Na₂SO₄and all volatiles evaporated in vacuo using a rotary evaporator.Un-purified yield: 1.42 g yellow/brownish oil. The oil was purified bycolumn chromatography (80 g silica; eluent: DCM (A)/10% methanol in DCM(B); gradient: t=0 min. 0% B, t=5 min. 5% B, t=20 min. 20% B). Yield:1.33 g slightly yellow oil (95% yield). LC-MS: purity 97%, [M+H]=287.¹H-NMR δ (400 MHz, CDCl₃): 6.34-6.23 (m, 2H), 6.17-6.05 (m, 1H), 5.30(s, 1H), 4.79 (s, 1H), 3.20 (d, J=10.9 Hz, 1H), 2.50-2.37 (m, 2H),2.23-2.12 (m, 2H), 1.96-1.87 (m, 2H), 1.77-1.64 (m, 4H), 1.64-1.49 (m,2H), 1.45-1.36 (m, 3H), 1.09 (s, 2H), 0.91 (t, J=7.3 Hz, 3H).

The ring-closure via compound [9] followed by removal of the twobromides to form compound [10] was performed. To avoid the observedstability issues, compound [9] was not isolated but used directly as asolution in DCM. A solution of compound [7] (200 mg) in DCM was treatedwith 1.2 equivalents of BF₃ etherate at −10° C. LC-MS showed theformation of a new product (the mass of compounds [7] and [9] are thesame and thus gives no additional information about the conversion atthis point). After a total reaction time of 45 minutes, the mixture wasquenched with water and the layers were separated. The organic phase wasused as such in the debromination-reaction.

After the addition of methanol, an aqueous solution of Na₂SO₃ (2.65 eq.)and L-ascorbic acid (0.15 eq.) was added, followed by triethylamine (3.6eq.). The mixture was heated to 40° C. and the conversion was monitoredby LC-MS. After 2 hours at this temperature, no conversion was observed.The temperature was increased to 75° C. and the mixture was stirred for1 hour. Again, no significant conversion was detected. Stirring wascontinued overnight and subsequent analysis with LC-MS showed theformation of a new product with the correct retention time and mass of[10]. After aqueous work-up, 85 mg of a yellow oil was obtained (65%yield over two steps, not corrected for the purity) with a purity of78%. The formation of [10] via the sequence [7]-[9]-[10] wasdemonstrated.

Synthesis of(6aS,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol[10]

To a cold (−10° C.) solution of boron trifluoride etherate (ca. 48% BF₃,77 mg, 0.540 mmol, 0.068 ml) in dichloromethane (2 mL) was slowly addeda solution of(1′R,2′R)-3,5-dibromo-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol(200 mg, 0.450 mmol) in dichloromethane (2 ml) in 15 minutes. Afterstirring for 60 minutes, the reaction was quenched by addition of water(2 mL). The formed slurry was diluted with extra DCM (2 mL) and thelayers were separated using a phase separator. To the organic phase wasadded methanol (2 mL) and a solution of sodium sulfite (150 mg, 1.193mmol) and L-ascorbic acid (11.89 mg, 0.068 mmol) in water (2 mL). Atroom temperature, added triethylamine (164 mg, 1.621 mmol, 0.225 ml) inone portion, heated the mixture to 75° C. and stirred overnight. Aftercooling to room temperature, the reaction mixture was partiallyconcentrated in vacuo, using a rotary evaporator, to remove most of themethanol and volatiles. The pH of the remaining aqueous phase wasadjusted to ˜4 with 3M aq. hydrochloric acid. DCM (5 mL) was added andthe mixture was stirred for 30 minutes. The layers were separated andremaining aqueous phase was extracted with DCM (5 mL). The layers wereseparated and the combined organic phases were dried with a phaseseparator. All volatiles were evaporated in vacuo using a rotaryevaporator. Yield: 85 mg yellow oil (66% yield). LC-MS: purity 78%,[M+H]=287. ¹H-NMR δ (400 MHz, CDCl₃): 6.34-6.23 (m, 2H), 6.17-6.05 (m,1H), 5.30 (s, 1H), 4.79 (s, 1H), 3.20 (d, J=10.9 Hz, 1H), 2.50-2.37 (m,2H), 2.23-2.12 (m, 2H), 1.96-1.87 (m, 2H), 1.77-1.64 (m, 4H), 1.64-1.49(m, 2H), 1.45-1.36 (m, 3H), 1.09 (s, 2H), 0.91 (t, J=7.3 Hz, 3H).

Adding chloride as protection group: The chlorination of olivetoltowards cannabidiol was performed as shown in FIG. 6. A solution ofolivetol (1 g) in DCM was treated with 2 equivalents of sulfurylchloride using a dropping funnel at 0° C. After 1 hour, a new productwith the correct mass was formed, as well as a large amount ofmono-chlorinated material. The starting material was no longer detectedby LC-MS. The reaction was continued in time and small aliquots ofsulfuryl chloride were added to drive the reaction to completion. Afterthe addition of 3 equivalents of sulfuryl chloride in total, a smallamount of the tri-chloro compound was also formed. No work-up wasperformed in this experiment.

The reaction was repeated on 1 g scale. The sulfuryl chloride (2.25equivalents) was slowly dosed into the reaction mixture in a controlledmanner using a syringe pump. A second aliquot of sulfuryl chloride (0.5equivalent) was added to drive the reaction to ca. 95% conversion. Afteraqueous work-up, a yellowish oil was obtained that spontaneouslysolidified. A quick purification by column chromatography resulted inthe complete removal of the remaining 5% mono-chlorinated compound and[11] was obtained as a colorless oil (0.88 g, 64%) that spontaneouslysolidified. Analysis with LC-MS showed the purity to be >95% andconfirmed the mass of the intended product. Analysis with 1H-NMRconfirmed the structure.

The synthesis was repeated on 25 g scale and a complete conversion wasachieved. After aqueous work-up, the obtained brown oil (31.1 g) wasdissolved in heptane (100 mL) and stored at 4° C. overnight, whichresulted in the formation of white crystals. These were filtered off anddried on the filter to yield [11] (22.4 g, 65% yield and 98% purityaccording to LC-MS). The structure was confirmed with ¹³C-APT-NMRspectroscopy.

Synthesis of 4,6-dichloro-5-pentylbenzene-1,3-diol [11]

To a cold (0° C.) solution of 5-pentylbenzene-1,3-diol (25 g, 139 mmol)in dichloromethane (250 ml) was slowly added sulfuryl chloride (46.8 g,347 mmol, 28.1 ml) over a 30 minute period. The resulting mixture wasstirred over night while slowly warming to room temperature. Thereaction mixture was quenched with 1M aq. NaOH (150 mL) and subsequentlystirred for 15 minutes. The formed slurry was diluted with extra DCM(100 mL) and then acidified to pH ˜3 with 3M aq. HCl. The layers wereseparated and the aqueous phase was extracted once with DCM (150 mL).The combined organic layers were dried on Na₂SO₄ and all volatilesevaporated in vacuo using a rotary evaporator. Un-purified 31.1 gbrown/yellow oil. The oil was dissolved in heptane (100 mL) and storedthe solution at 4° C. The formed crystals were filtered off and thendried on filter by air stream. Yield: 22.4 g slightly yellow solid (65%yield). LC-MS: purity 98%, [M−H]=247. ¹H-NMR δ (400 MHz, CDCl₃): 6.62(s, 1H), 5.61 (s, 2H), 2.90-2.81 (m, 2H), 1.62-1.50 (m, 2H), 1.45-1.31(m, 4H), 0.92 (t, J=7.0 Hz, 3H).

The coupling with menthadienol towards(1′R,2′R)-3,5-dichloro-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol[12] was investigated on 1 g scale. Using the same conditions as usedfor the bromide-analogue, [11] was coupled with menthadienol (1equivalent) at −35° C. using p-toluenesulfonic acid (0.5 eq.). Thereaction was monitored with LC-MS and two further aliquots ofmenthadienol were added (0.3 and 0.15 eq.) over the course of 4 hours. Amixture of starting material (22%), product (56%) and a possibleintermediate (22%) was obtained. The reaction was then allowed to slowlywarm to room temperature overnight. Upon warming, an unknown product(50%) was formed presumably the already ring-closed product, analogousto the bromide. The remainder of the mixture was mainly product (42%).

The experiment was repeated on 1 g scale and the reaction was monitoredcarefully over time. Again, several aliquots of menthadienol were added.After a total reaction time of 5 hours, the reaction was stillincomplete. After aqueous work-up and subsequent purification by columnchromatography to remove the unreacted material, 1.06 g of [11] wasobtained as a colorless oil (66% yield) with a purity of >98% accordingto LC-MS.

Synthesis of(1′R,2′R)-3,5-dichloro-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol[12]

A mixture of 4,6-dichloro-5-propylbenzene-1,3-diol (1 g, 4.52 mmol),(1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol (0.689 g, 4.52 mmol)and magnesium sulfate (1.361 g, 11.31 mmol) in dichloromethane (10 mL)was cooled to −35° C. Then, p-toluenesulfonic acid monohydrate (0.430 g,2.262 mmol) was added in one portion and the mixture was stirred for 90minutes. A second aliquot of(1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol (0.207 g, 1.357 mmol)was added and the mixture was stirred for 90 minutes. A third aliquot of(1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol (0.103 g, 0.678 mmolwas added and the mixture was stirred for 5.5 hours. A fourth aliquot of(1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol (0.103 g, 0.678 mmol)was added and the mixture was stirred for 90 minutes. The reactionmixture was quenched by pouring into a solution of dibasic potassiumphosphate, (0.709 g, 4.07 mmol) in water (10.0 mL). The layers wereseparated with a phase separator and the organic phase was evaporated invacuo using a rotary evaporator. The obtained oil was stirred inmethanol (5 mL) at 0° C. for 1 hour, then all undissolved solids werefiltered off using a folded paper filter. Un-purified yield: 1.06 galmost colorless oil. The oil was purified by column chromatography (120g silica; eluent: heptane (A)/ethyl acetate (B); gradient: t=0 min. 0%B, t=25 min. 10% B). Yield: 0.44 g colorless oil (27% yield). LC-MS:purity 100%, [M−H]=381. ¹H-NMR δ (400 MHz, CDCl₃): 6.39 (s, 1H), 5.60(s, 1H), 5.46 (s, 1H), 4.53 (s, 1H), 4.42 (s, 1H), 4.08-3.98 (m, 1H),2.90-2.75 (m, 2H), 2.62-2.51 (m, 1H), 2.31-2.16 (m, 1H), 2.14-2.03 (m,1H), 1.87-1.72 (m, 5H), 1.68 (s, 3H), 1.60-1.46 (m, 2H), 1.44-1.29 (m,4H), 0.91 (t, J=6.9 Hz, 3H).

For the dechlorination step, [11] was used as a model compound sinceonly a limited amount of [12] was obtained. The same conditions for thedebromination (Na₂SO₃ (2.65 eq.), L-ascorbic acid (0.15 eq.),triethylamine (3.6 eq.), a methanol/water mixture, 75° C.) were appliedon [11] on 250 mg scale. After stirring for 1 hour, no conversion wasobserved. After stirring overnight, some decomposition was observed.

The dechlorination step was repeated using the same scale and conditionsbut using 2-propanol instead of methanol. The reaction temperature wasincreased to 100° C. No conversion was achieved after stirringovernight. No decomposition was detected after reacting overnight.

The dechlorination step was repeated using triethylsilane mediated,Pd₂(d-t-bppf)Cl₂ catalyzed reaction conditions as described in Tet.Lett., 2013, 54, 4518-4521. A degassed solution of [11] (250 mg) indioxane was treated with triethylsilane (5 eq.), triethylamine (2 eq.)and Pd₂(d-t-bppf)Cl₂ (5 mol %). After stirring for 1 hour at 100° C.,near complete conversion into a new product was observed with LC-MS.After aqueous work-up, the newly formed product could not be isolatednor detected in significant amounts in either the organic or aqueousphase.

[12] was used for the dechlorination step. A solution of compound [12](100 mg) in dioxane was treated with triethylsilane (5 eq.),triethylamine (2 eq.) and Pd₂(d-t-bppf)Cl₂ (5 mol %). After stirring at100° C. overnight, partial conversion into a new product was observedwith LC-MS with 36% starting material remaining, 44% of a new andunknown product and only 6% of a product with the correct retention timeof the fully dechlorinated cannabidiol). The compounds did not ionizeproperly on the LC-MS systems and no useful mass traces were obtained.

The removal of the chloride protection groups was tested by catalytichydrogenation. A solution of [11] (60 mg) in methanol (1 mL) was treatedwith palladium on carbon (5 mg, 10% metal loading) under hydrogenatmosphere at ambient pressure. After stirring for 2 hours, partialconversion into a new product was observed with LC-MS but no mass wasobserved in the mass trace. After stirring overnight a completeconversion was achieved. Subsequent filtration to remove the catalystand evaporation of the solvent yielded 40 mg of a yellowish oil.Analysis with ¹H-NMR revealed that the characteristic protons of thedouble bond were no longer present and also no increase in the number ofaromatic signals was found.

Adding iodide as protection group: The iodination of olivetol towardscannabidiol was performed as shown in FIG. 7. Olivetol (100 mg) wastreated with N-iodosaccharin (2.1 equivalents) in MeCN at roomtemperature. After stirring overnight, a complete conversion wasobserved with LC-MS and the correct mass was found in the mass trace butseveral unknown other signals were observed as well, one of thempresumably being the saccharine residue.

After evaporation of the solvent in vacuo and subsequent trituration inmethanol to remove most of the solid saccharin residue, the obtainedclear filtrate was evaporated in vacuo to yield 234 mg of an orange/redoil that still contained some solids. This material was further purifiedby Reveleris® column chromatography using silica and heptane/ethylacetate as eluent to yield a colorless oil (108 mg, 45% yield) thatsolidified upon scratching with a spatula. Analysis with LC-MS showedthe purity to be >98% and the structure was confirmed with ¹H-NMR.

Repetition of the synthesis of 4,6-diiodo-5-pentylbenzene-1,3-diol [13]on 1.25 g scale was performed. After evaporation of the solvent in vacuoand subsequent trituration in methanol to remove most of the solidsaccharin residue, the obtained clear filtrate was evaporated in vacuoand then further purified by Reveleris® column chromatography usingsilica and heptane/ethyl acetate as eluent to yield a colorless oil(1.70, 57% yield), which solidified spontaneously. Analysis with LC-MSshowed the purity to be 97%.

Synthesis of 4,6-diiodo-5-pentylbenzene-1,3-diol [13]

A mixture of 5-pentylbenzene-1,3-diol (1.25 g, 6.94 mmol) andN-iodosaccharin (4.50 g, 14.56 mmol) in acetonitrile (anhydrous, 12.5mL) was stirred overnight (in darkness). All volatiles were evaporatedin vacuo using a rotary evaporator and the obtained residue was stirredin a minimal amount of methanol overnight. The undissolved material wasfiltered off and the filtrate was evaporated in vacuo using a rotaryevaporator. The oil was purified by column chromatography (120 g silica;eluent: heptane (A)/ethyl acetate (B); gradient: t=0 min. 1% B, t=5 min.1% B, t=30 min. 5% B). Yield: 1.70 g colorless oil (57% yield). The oilsolidified spontaneously. LC-MS: purity 98%, [M−H]=430. ¹H-NMR δ (400MHz, CDCl₃): 6.56 (s, 1H), 5.94 (s, 1H), 5.39 (s, 1H), 2.71-2.57 (m,2H), 1.64-1.47 (m, 2H), 1.46-1.23 (m, 4H), 1.00-0.81 (m, 3H).

The reaction of [13] with menthadienol was performed on 100 mg scale.After multiple additions of menthadienol, increasing the temperature to40° C. and stirring overnight, a large amount of [13] was found by LC-MSand the mass of(1′R,2′R)-3,5-diiodo-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol[14] was not detected in the mass trace. The reaction was repeated with1 equivalent of p-Tos-OH (compared to the normal 0.5 eq.) but noconversion was seen.

Different Lewis acids were screened on 50 mg scale. Glass vials werecharged with iodide [13] (50 mg), magnesium sulfate (3 eq.) and theLewis acid to be tested (1 eq.). The vials were placed in a pre-cooledreaction block at −35° C. A pre-cooled solution of menthadienol (2 eq.)in dichloromethane (1 mL) was added to each vial. The vials were stirredat −35° C. for 2 hours and samples (20 uL) were taken from each vial andsubsequently analysed with HPLC. Table 2 lists the results. Noconditions were found to couple [13] with menthadienol. Di-iodide isfound to be not reactive toward menthadienol.

TABLE 2 Overview of Lewis acid screening. Lewis acid Results Lithiumchloride No conversion Nickel(II)chloride No conversionCopper(II)chloride No conversion Copper(I)chloride No conversion Zincchloride No conversion Iron(II)chloride No conversion Iron(III)chlorideNo conversion Manganese(II)chloride No conversion Cerium(III)chloride Noconversion Cobalt(II)chloride No conversion Indium(III)chloride Noconversion Bismuth(III)chloride No conversion Samarium(III)chloride Noconversion

Overall, 5-propylbenzene-1,3-diol (the C3-olivetol analogue) prepared inExample 2 was successfully di-halo protected using bromide protectiongroups. Using the bromide protection groups both(1′R,2′R)-5′-methyl-2′-(prop-1-en-2-yl)-4-propyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol(the C3-cannabidiol-analogue) and(6aS,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(the C3-THC analogue) were prepared with two different syntheticpathways demonstrated for the C3-THC analogue. The syntheses proceededsimilarly to the C5-isomer. The synthesis of dichloro-olivetol anddiiodo-olivetol using the C5-isomer was also performed successfully.Subsequent coupling with menthadienol was successful for thedichloro-olivetol, but not for the diiodo-olivetol.

Example 4—Reaction of Dibromo-Olivetol with Other Olefins

The coupling of dibromo-olivetol with other olefins was performed.Dibromo-olivetol was coupled with the compounds in FIG. 8, includingcyclohexene, octane, cyclohex-2-enol and linalool. A mixture ofdibromo-olivetol (250 mg), the olefin to be coupled (1 eq.), magnesiumsulfate (2.5 eq.) in DCM (2.5 mL) was treated with p-Tos-OH (0.5 eq.) atroom temperature. After stirring for 2 hours, no conversion was observedwith LC-MS, except for the experiment in which cyclohex-2-enol was usedas coupling partner.

Using cyclohex-2-enol, full conversion into a new product was observed.After a simple aqueous work-up, the experiment with cyclohex-2-enol ascoupling partner yielded 223 mg of a brownish oil with a purity of 94%according to LC-MS. In the mass trace, a mass of [M−H]=417 was found.Combined with the structural data obtained from the ¹H-NMR spectrum itis believed that the formed compound is(S)-3,5-dibromo-4-pentyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol,the structure of which is shown in FIG. 9.

The coupling of dibromo-olivetol with linalool was repeated using THF assolvent so that a higher reaction temperature could be achieved. Theamount of p-Tos-OH was also reduced to 0.1 eq. to prevent potential sidereactions and/or decomposition. LC-MS indicated formation of a newproduct with still 47% starting material remaining after reactingovernight at 65° C. After aqueous work-up, the starting material wasrecovered with a purity of 73% according to LC-MS.

The coupling of dibromo-olivetol (C5-analogue) with different olefinshas proven feasible. The coupling of dibromo-olivetol, and relatedcompounds, can be performed using a cyclic olefin containing a doublebond and a hydroxy-group at a conjugated position. In some embodiments,the olefin can be any olefin as described herein, provided the olefin isnot cyclohexene, octane, linalool or combinations thereof.

Synthesis of3,5-dibromo-4-pentyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol

To a mixture of 4,6-dibromo-5-pentylbenzene-1,3-diol (0.25 g, 0.740mmol), cyclohex-2-enol (0.073 g, 0.740 mmol) and magnesium sulfate(0.223 g, 1.849 mmol) in dichloromethane (2.5 ml) was addedp-toluenesulfonic acid monohydrate (0.070 g, 0.370 mmol) in one portionat room temperature. The resulting mixture was stirred overnight andthen quenched with a solution of dibasic potassium phosphate, (0.116 g,0.666 mmol) in water (2.5 ml). The layers were separated with a phaseseparator and the organic phase was evaporated in vacuo using a rotaryevaporator. Yield: 223 mg brownish oil (69% yield). LC-MS: purity 94%,[M−H]=417. ¹H-NMR δ (400 MHz, CDCl₃): 6.48-5.92 (m, 3H), 5.83 (d, J=10.0Hz, 1H), 4.13-4.03 (m, 1H), 2.99-2.87 (m, 2H), 2.21-2.09 (m, 2H),2.01-1.82 (m, 2H), 1.79-1.62 (m, 2H), 1.61-1.49 (m, 2H), 1.48-1.32 (m,4H), 0.93 (t, J=7.0 Hz, 3H).

Example 5—Synthesis of(1R,2R,4S)-2-(dimethylamino)-1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol

To a solution of (−)-limonene oxide (39.73 g, 261 mmol) in ethanol (70mL) was added a 40% solution of dimethylamine in water (62.3 g, 553mmol, 70 mL). The mixture was heated to 65° C. and stirred for 26 hours.A clear yellow solution was formed. The mixture was allowed to cool toroom temperature and all volatiles evaporated in vacuo using a rotaryevaporator. The mixture was taken up in MTBE (90 mL) and washed withwater (30 mL). The solution was then dried over Na₂SO₄, filtered and theresidue washed with MTBE (20 mL). To the resulting solution was slowlyadded a solution of oxalic acid (10.28 g, 114 mmol) in acetone (40 mL)forming a thick white precipitate which required mechanical stirring.The precipitate was heated to reflux for 30 min. After cooling to roomtemperature and stirring for 2 hours the precipitate was filtered andthe residue washed with MTBE (100 mL). The resulting white hydroscopicsolid was transferred back into the reaction vessel and suspended in 30mL ethanol. The suspension was heated to reflux forming a yellowemulsion. MTBE (150 mL) was added dropwise forming a white precipitate.The suspension was allowed to cool to room temperature and stirredovernight. The suspension was filtered and washed twice withMTBE:ethanol (4:1, 50 mL). The resulting white solid was dissolved inwater (71 mL) and MTBE (55 mL). Under vigorous stirring a 2N solution ofKOH was added (130 mL). The phases were separated, the organic phase wasdried over Na₂SO₄ and concentrated in vacuo. Yield: 20.96 g of acolourless oil (40.7% yield). GCMS: purity 98.9%, [M]=197.

Example 6—Synthesis of(1R,4S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol(1R,4S-menthadienol)

A solution of(1R,2R,4S)-2-(dimethylamino)-1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol(24.68 g, 125 mmol) in ethanol (50 mL) was heated to reflux. Uponreaching reflux a solution of hydrogen peroxide (17.76 g, 157 mmol, 30%)was added dropwise. After complete addition the mixture was refluxed for2.5 hours. After cooling to room temperature the reaction was quenchedby addition of sodium sulfite (5.12 g, 40.6 mmol) in water (18 mL).After a peroxide teststrip revealed no peroxides were present thereaction mixture was diluted with acetone (60 mL) resulting in a whitesuspension. The precipitate was removed by filtration and the residuewashed with acetone (60 mL). Concentration in vacuo using a rotaryevaporator resulted in 30.05 g of the N-oxide as a yellow oil. TheN-oxide was transferred to a Kugelrohl flask and subsequently pyrolyzedat 160 C at 15 mBar pressure. The clear oil slowly turned orange andafter complete removal of solvents solidified to an orange solid whichmelted upon further heating. A clear oil was collected which wasdissolved in MTBE (60 mL) and washed with water (16 mL) followed bywashing with a cooled solution of 1% sulfuric acid (1×16 mL, 2×10 mL).The organic phase was then washed with satd. NaHCO₃ solution (2 mL),subsequently dried over Na₂SO₄ and concentrated in vacuo using a rotaryevaporator. Yield: 15.15 g of a colourless oil (80% yield). GCMS: purity95%, [M]=152. Chiral HPLC: enantiomeric excess 99%.

Example 7—Synthesis of(1′S,2′S)-3,5-dibromo-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol

A mixture of 4,6-dibromo-5-pentylbenzene-1,3-diol (16.2 g, 43.6 mmol),(1R,4S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (4.35 g, 28.6mmol) and magnesium sulfate (15 g, 125 mmol) in dichloromethane (100 mL)was cooled to −30° C. Then, p-toluenesulfonic acid monohydrate (4.19 g,22.03 mmol) was added in one portion and the resulting mixture wasstirred at −30° C. The reaction was monitored with LCMS and over thecourse of 5 hours, extra aliquots of(1R,4S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (4.26 g, 27.9 mmoland 1.95 g, 12.8 mmol respectively) were added before stirring themixture at −30° C. The reaction mixture was poured into a solution ofdibasic potassium phosphate (7.60 g, 43.6 mmol) in water (150 mL) andthe layers were separated. The aqueous phase was extracted with DCM (40mL) and the combined organic layers were concentrated to dryness invacuo using a rotary evaporator. The obtained oil was dissolved inmethanol (150 mL) and then stirred for 1.5 hours at −15° C. A whitesolid was removed by filtration and was discarded. The filtratecontaining the product was used as is in the next reaction step. LCMS:purity 77%, [M+H]=471.

Example 8—Synthesis of(1′S,2′S)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol

To a solution of(1′S,2′S)-3,5-dibromo-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol(assumed 20.59 g, 43.6 mmol) in methanol (180 ml) was added a solutionof sodium sulfite (15.92 g, 126 mmol) and L-ascorbic acid (1.24 g, 0.608mmol) in water (150 mL). A yellow suspension was formed, triethylamine(17.42 g, 172 mmol, 24 ml) was added in one portion. The resultingmixture was heated to 70° C. for 22 hours, subsequently 62 g of solventwere removed by disstillation at 90° C. After cooling to roomtemperature the pH of the remaining aqueous phase was adjusted to ˜4with concentrated hydrochloric acid. Heptane (40 mL) was added and themixture was stirred for 30 minutes. The layers were separated, theorganic phase was washed with brine (20 mL) and dried over Na₂SO₄. Theresulting brown solution was cooled to −20° C. in attempts tocrystallize the material. After several attempts at cooling, furtherconcentration and recooling. A sample was cooled on dry ice undervigorous scratching, forming white crystals. These were used to seed theremaining solution which immediately crystallized. Yield: 7.65 g ofoff-white crystals (55% yield). LCMS: purity 99.3%, [M+H]=315. ChiralHPLC: enantiomeric excess 99%. ¹H-NMR δ (400 MHz, CDCl₃): 6.40-6.10 (br,2H), 6.00 (br, 1H), 5.57 (s, 1H), 4.79 (br, 1H), 4.65 (s, 1H), 4.55 (s,1H), 3.90-3.10 (m, 1H), 2.46-2.36 (m, 3H), 2.29-2.17 (m, 1H), 2.14-2.05(m, 1H), 1.87-1.71 (m, 5H), 1.66 (s, 3H), 1.55 (p, J=7.6 Hz, 2H),1.37-1.22 (m, 4H), 0.87 (t, J=7.0 Hz, 3H).

While this disclosure has been particularly shown and described withreference to example embodiments thereof, it will be understood by thoseskilled in the art that various changes in form and details may be madetherein without departing from the scope of the invention encompassed bythe appended claims.

We claim: 1.-20. (canceled)
 21. A composition comprising a compound offormula (XVI):

or a pharmaceutically acceptable salt thereof, wherein said compositioncomprises at least 99.96 area % of the compound of formula (XVI) andless than 0.04 area % of 4,6-dihalo-5-pentylbenzene-1,3-diol,4-halo-5-pentylbenzene-1,3-diol, 6-halo-5-pentylbenzene-1,3-diol, anddelta-9-tetrahydrocannabinol.
 22. The composition of claim 21, whereinsaid composition is a white crystalline powder.
 23. The composition ofclaim 21, wherein said halo is chloro or bromo.
 24. The composition ofclaim 23, wherein said halo is bromo.
 25. The composition of claim 24,comprising a compound of formula (XVI):

or a pharmaceutically acceptable salt thereof, wherein said compositioncomprises at least 99.96 area % of the compound of formula (XVI) andless than 0.04 area % of 4-bromo-5-pentylbenzene-1,3-diol,6-bromo-5-pentylbenzene-1,3-diol, and delta-9-tetrahydrocannabinol. 26.The composition of claim 21, wherein said compound of formula (XVI) hasan enantiomeric excess of at least about 99%.
 27. A compositioncomprising a compound of formula (XVI):

or a pharmaceutically acceptable salt thereof; wherein said compositioncomprises no more than 400 ppm of 4,6-dihalo-5-pentylbenzene-1,3-diol,4-halo-5-pentylbenzene-1,3-diol, 6-halo-5-pentylbenzene-1,3-diol, anddelta-9-tetrahydrocannabinol.
 28. The composition of claim 27, whereinsaid halo is chloro or bromo.
 29. The composition of claim 28, whereinsaid halo is bromo.
 30. The composition of claim 29, comprising no morethan 400 ppm of 4-bromo-5-pentylbenzene-1,3-diol,6-bromo-5-pentylbenzene-1,3-diol, and delta-9-tetrahydrocannabinol 31.The composition of claim 27, wherein said composition is a whitecrystalline powder.
 32. The composition of claim 27, wherein saidcompound of formula (XVI) has an enantiomeric excess of at least about99%.